WO2022180809A1 - Therapeutic for lung cancer that has acquired resistance to type 1 anticancer drugs - Google Patents
Therapeutic for lung cancer that has acquired resistance to type 1 anticancer drugs Download PDFInfo
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- WO2022180809A1 WO2022180809A1 PCT/JP2021/007458 JP2021007458W WO2022180809A1 WO 2022180809 A1 WO2022180809 A1 WO 2022180809A1 JP 2021007458 W JP2021007458 W JP 2021007458W WO 2022180809 A1 WO2022180809 A1 WO 2022180809A1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to a therapeutic drug that overcomes secondary resistance mutations and treats lung cancers that have developed resistance secondary mutations to type I MET tyrosine kinase inhibitors. More specifically, a type I MET tyrosine kinase inhibitor is administered to lung cancer with MET exon 14 skip, and the aspartic acid (D) at position 1228 and tyrosine (Y) at position 1230 of c-Met
- the present invention relates to a drug capable of overcoming resistance and treating lung cancer that has acquired resistance to type I MET tyrosine kinase inhibitors due to mutations in any of them.
- MET is a hepatocyte growth factor (HGF) receptor with tyrosine kinase activity, and its genetic abnormalities have been reported in various cancer types.
- HGF hepatocyte growth factor
- MET exon 14 skipping mutation (hereinafter referred to as "METex14”) is one of MET gene abnormalities and is found in about 3% of non-small cell lung cancer (NSCLC).
- MET-TKIs MET tyrosine kinase inhibitors
- capmatinib US and Japan
- tepotinib Japan
- Approved capmatinib and tepotinib are classified as type I inhibitors that bind to the activated state of MET. Then, by experiments using an artificial tumor cell model having METex14, Asp1228 (D1228: 1228th aspartic acid) and Tyr1230 (Y1230: 1230th tyrosine) as a resistance mechanism to type I MET tyrosine kinase inhibitors It has been reported that secondary mutations often occur (Non-Patent Document 2).
- Non-Patent Document 3 the mutations at D1228 and Y1230 can be used as indicators indicating that METex14-positive lung cancer patients have resistance to type I MET tyrosine kinase inhibitors.
- the present invention has been conceived in view of the above problems, and provides a new class of MET-TKIs for lung cancer that can overcome acquired resistance to capmatinib or tepotinib.
- the therapeutic drug for lung cancer according to the present invention is Expression (1) against lung cancer exhibiting MET_exon14_Skipping mutation and in which amino acids 1228 and 1230 of c-Met are mutated to amino acids other than aspartic acid and tyrosine (type I MET-TKI-resistant lung cancer) and (2) is a therapeutic drug for lung cancer containing as an active ingredient any one of the compounds of the formulas.
- the present invention provides a method for lung cancer having Met_exon14_Skipping and c-Met at amino acids 1228 and 1230 mutated to amino acids other than aspartic acid and tyrosine, respectively, in formulas (1) and (2). It may also be said that treatment using a drug containing any of the compounds as an active ingredient.
- the therapeutic drug for lung cancer containing the compound of formula (1) or formula (2) according to the present invention as an active ingredient has a METex14 mutation, and amino acids 1228 and 1230 of c-Met are other than aspartic acid and tyrosine, respectively. It is effective in suppressing the cell growth of lung cancer with amino acid mutations, that is, lung cancer that is positive for METex14 and has acquired resistance to type I MET-TKI.
- lung cancer caused by METex14 is said to occur at the same frequency as lung cancer caused by ALK fusion gene mutation.
- ALK-TKI ALK tyrosine kinase inhibitors
- 5 types of ALK tyrosine kinase inhibitors (ALK-TKI) with different mechanisms have already been developed and marketed, and even if resistance to the first used ALK-TKI is acquired, another ALK - Switching to TKIs has overcome resistance and improved prognosis. Therefore, it is highly expected that a therapeutic agent that overcomes resistance to type I MET-TKI-positive lung cancer that is positive for METex14 will be commercially successful.
- FIG. 10 shows the relationship between drug concentration and cell viability when cabozantinib is administered to Ba/F3 cells in which aspartic acid (D) at position 1228 of c-Met is mutated to asparagine (N).
- the therapeutic agent for lung cancer contains compounds represented by formulas (1) and (2) as active ingredients. These compounds are a method of finding drugs that exhibit inhibitory activity from drug libraries with various mechanisms of action using cell models that have secondary mutations that are predicted to appear as resistance mutations to type I MET-TKIs. It was found in Type I MET-TKI is a drug that exhibits inhibitory action by binding to the DFG-in structure of tyrosine kinase.
- Type II MET-TKIs are drugs that exhibit an inhibitory action by binding to the DFG-out structure of tyrosine kinases. That is, it has a different mechanism of action from type I MET-TKIs, and is likely to be able to overcome resistance to type I MET-TKIs.
- the METex14 mutation-positive lung cancer that has acquired resistance to type I MET-TKI (MET tyrosine kinase inhibitor) also has the effect of overcoming resistance and suppressing cancer cell proliferation.
- MET-TKI MET tyrosine kinase inhibitor
- a drug containing the compound of formula (1) or formula (2) as an active ingredient can be used to treat METex14 mutation-positive lung cancer that has acquired resistance to type I MET-TKIs.
- foretinib of formula (1) can be administered to humans as a pharmaceutically acceptable salt.
- it can be administered as the free base.
- foretinib can be administered, for example, at doses of about 7.5 mg, 15.0 mg, 30.0 mg, and/or 45.0 mg daily.
- foretinib may be provided in tablet form.
- the tablet may contain hypromellose, sodium lauryl sulfate, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.
- Some tablets may also contain hypromellose, titanium dioxide, polyethylene glycol. Additionally, the tablets may contain polysorbate 80 and yellow iron oxide.
- Foretinib can be prepared as described in International Application No. PCT/US2009/064341, which has an international filing date of November 13, 2008 and an international publication number of WO 2010/056960; The international publication date is May 20, 2010.
- Foretinib can be prepared as described in International Application No. PCT/US2009/058276, which has an international filing date of September 25, 2009 and an international publication number of WO 2010/036831; The international publication date is April 1, 2010.
- CEP-40783 or a pharmaceutically acceptable salt thereof can be administered in a wide variety of oral and/or parenteral dosage forms.
- the compounds of the invention are delivered orally.
- Parenteral administration can be by injection, ie, intravenous, intramuscular, intradermal, subcutaneous, intraduodenal, or intraperitoneal.
- CEP-40783 or a pharmaceutically acceptable salt thereof is also administered intravenously or subcutaneously.
- CEP-40783, or a pharmaceutically acceptable salt thereof can also be administered by inhalation, eg intranasally, as well as transdermally.
- CEP-40783, or a pharmaceutically acceptable salt thereof can also be delivered rectally, by buccal tablets, or by insufflation.
- Determination of the appropriate dosage of CEP-40783, or a pharmaceutically acceptable salt thereof, for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. Suitably, the total daily dosage may be divided and administered in portions during the day, if desired.
- CEP-40783 or a salt thereof can be administered 1 to 4 times per day.
- a typical dose is about 1 mg to about 1,000 mg (eg, about 5 mg to about 500 mg).
- a standard dose is about 1 mg to about 300 mg (eg, about 5 mg to about 250 mg). In still other cases, a standard dose may be about 10 mg to 100 mg.
- CEP-40783 or its salt is administered according to body weight.
- You may CEP-40783 or a salt thereof can also be administered in an amount of about 10 mg/kg to about 55 mg/kg.
- CEP-40783 can be prepared using any number of different methods, for example, using the methods described in WO2013/0074633.
- Ba/F3 cells are mouse-derived proB cells that normally require exogenous interleukin 3 (IL3) for their survival.
- IL3 interleukin 3
- Ba/F3 cells were established that showed survival and proliferation depending only on the MET exon 14 skipping gene mutation. These are called METex14-Ba/F3 cells.
- capmatinib or tepotinib By administering capmatinib or tepotinib on a 96-well plate and culturing in its presence for about 3 weeks, a mutation was induced in the tyrosine kinase binding site of MET to prepare a resistant cell line.
- the kinase regions of the obtained resistant strains were analyzed by the Sanger sequencing method, the types of secondary mutations were investigated, and cells with each mutation were established.
- aspartic acid (D) at position 1228 of c-Met in METex14-Ba/F3 cells is replaced by alanine (A), glutamic acid (E), glycine (G), histidine (H), asparagine (N), and valine. (V), METex14-Ba/F3 cells mutated to tyrosine (Y) were obtained.
- the respective cell lines are simply called D1228A, D1228E, D1228G, D1228H, D1228N, D1228V, D1228Y.
- tyrosine (Y) at position 1230 of c-Met in METex14-Ba/F3 cells was mutated to cysteine (C), aspartic acid (D), histidine (H), asparagine (N), and serine (S).
- METex14-Ba/F3 cells were also obtained. Each cell line is simply called Y1230C, Y1230D, Y1230H, Y1230N, Y1230S.
- sample cells It may also be referred to as "METex14-Ba/F3 resistant cells”.
- the cells are model cells that are resistant to type I MET-TKI. Also, it can be said that the cell is a cell in which the 1228th and 1230th amino acids of c-Met are mutated to amino acids other than aspartic acid (D) and tyrosine (Y). Furthermore, it is a model cell that has a METex14 mutation and has acquired resistance to capmatinib or tepotinib.
- example drugs 300 drugs with various mechanisms of action registered in the drug library (hereinafter referred to as “sample drugs”) are administered to overcome resistance and produce effects as MET-TKIs. I searched for drugs. The specific procedure was as follows.
- control well On the second day, all 300 drugs were administered at a concentration of 100 nM. In addition, DMSO was administered to 1 well per plate as a control. This well is called a "control well".
- METex14-Ba/F3 cells In three types of cells, METex14-Ba/F3 cells, D1228A, and D1228Y (both of which are METex14-Ba/F3-resistant cells), the survival rate was 50% or less compared to DMSO-administered control wells. were selected as candidate drugs. Drugs that showed effects also on normal Ba/F3 cells were excluded, judging that they did not show inhibitory effects specifically on MET signal. IC50 and viability were determined as follows.
- the survival rate for each sample drug was calculated as the ratio (percentage) of the number of viable cells in each well to the number of viable cells in the control wells, and a curve of viability versus sample drug concentration was created. An example of the graph is shown in FIG.
- Figure 1 is a graph of drug concentration (nM) - cell viability (%) when cabozantinib was administered to sample cells in which aspartic acid (D) at position 1228 of c-Met was mutated to asparagine (N). is.
- the horizontal axis is sample drug concentration (nM) and the vertical axis is viability (%). It can be seen that the sample drug concentration is approximately 37.04 nM and the cell viability is 50%. Based on such a graph, the drug concentration (IC50) at which the survival rate becomes 50% was calculated for each sample drug.
- Table 1 shows example results of sample drugs that were able to overcome resistance to secondary mutations and drugs that were not.
- each cell line is also called D1228A, D1228E, D1228G, D1228H, D1228N, D1228V, D1228Y, Y1230C, Y1230D, Y1230H, Y1230N, Y1230S.
- the first and second rows show the IC50 concentrations when capmatinib and tepotinib are administered as type I MET-TKIs.
- the third and fourth lines show the results of administering CEP-40783 and foretinib as type II MET-TKIs.
- the fourth and fifth rows show the results of cabozantinib and merestinib as Type II MET-TKIs.
- the type I MET-TKIs (capmatinib and tepotinib) had an IC50 of 0.6 nM and 3.0 nM against the parent strain of METex14, demonstrating an effective c-Met inhibitory effect.
- the IC50 was 100 nM or more for any secondary mutation.
- tepotinib had an IC50 higher than 1000 nM against all METex14-Ba/F3 mutant cells. That is, these type I MET-TKIs had no inhibitory effect on secondary mutant cells.
- the secondary mutated METex14-Ba/F3 mutant cells acquired resistance to these sample agents of type I type.
- the type II MET-TKIs cabozantinib and merestinib had a low IC50 of 30 nM or less when the 1230th tyrosine (Y) was mutated. In other words, it could be said that the c-Met inhibitory effect was exhibited by overcoming the resistance. However, when the 1228th aspartic acid (D) was mutated, the IC50 was often greater than 30 nM.
- CEP-40783 and foretinib which are type II MET-TKIs, for both the 1228th and 1230th mutations, the IC50 is 30 nM or less, and in most cases it is 10 nM or less. Indicated. In other words, it was concluded that these two drugs overcome the resistance to cells in which METex14 is expressed and in which the 1228th and 1230th amino acids are mutated, and exerts an inhibitory effect on MET tyrosine kinase.
- these two sample drugs can be used as drugs that can be used continuously after overcoming the resistance after the type I MET-TKI has become ineffective due to resistance.
- treatment using these drugs is effective against lung cancer in which METex14 is expressed and in which amino acids at positions 1228 and 1230 are mutated (type I type MET-TKI-resistant lung cancer). It can be said that it is possible.
- the therapeutic drug for lung cancer according to the present invention is effective against lung cancer in which METex14 is expressed and amino acids 1228 and 1230 are mutated (type I MET-TKI-resistant lung cancer). and can be expected to have the effect of suppressing the proliferation of cancer cells in vivo.
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Abstract
The type 1 MET tyrosine kinase inhibitors capmatinib and tepotinib are effective against lung cancer having an MET exon 14 skipping mutation and have been approved as first-line drugs in Japan and the US, but it is expected that resistance to both of these drugs will be acquired. However, there were no prospects for drugs that could be used next. Lung cancer therapeutics having as an active ingredient any compound of formula (1) and formula (2) can overcome resistance to capmatinib and tepotinib and manifest an effect as an inhibitor against lung cancer having an MET exon 14 skipping mutation in which the amino acids 1228 and 1230 of c-MET are mutated to an amino acid other than aspartic acid and tyrosine, respectively.
Description
本発明は、タイプI型METチロシンキナーゼ阻害剤に対して耐性二次変異を生じた肺癌に対して、耐性二次変異を克服し、肺癌を治療する治療薬に関する。より具体的には、MET exon 14 skipが生じた肺癌に対してタイプI型METチロシンキナーゼ阻害剤が投与され、c-Metの1228番目のアスパラギン酸(D)と1230番目のチロシン(Y)の何れかに変異を生じ、タイプI型METチロシンキナーゼ阻害剤に対して耐性を獲得した肺癌を、耐性を克服して治療できる薬剤に関するものである。
The present invention relates to a therapeutic drug that overcomes secondary resistance mutations and treats lung cancers that have developed resistance secondary mutations to type I MET tyrosine kinase inhibitors. More specifically, a type I MET tyrosine kinase inhibitor is administered to lung cancer with MET exon 14 skip, and the aspartic acid (D) at position 1228 and tyrosine (Y) at position 1230 of c-Met The present invention relates to a drug capable of overcoming resistance and treating lung cancer that has acquired resistance to type I MET tyrosine kinase inhibitors due to mutations in any of them.
METはチロシンキナーゼ活性を有する肝細胞増殖因子(HGF)の受容体であり、様々な癌種でその遺伝子異常が報告されている。MET exon 14 skipping変異(以下「METex14」と呼ぶ。)は、MET遺伝子異常の一つであり、非小細胞肺癌(NSCLC)の約3%に認められる。
MET is a hepatocyte growth factor (HGF) receptor with tyrosine kinase activity, and its genetic abnormalities have been reported in various cancer types. MET exon 14 skipping mutation (hereinafter referred to as "METex14") is one of MET gene abnormalities and is found in about 3% of non-small cell lung cancer (NSCLC).
2020年にはMETチロシンキナーゼ阻害薬(以下「MET-TKI」と記す。)としてカプマチニブ(capmatinib、米と日本)とテポチニブ(tepotinib、日本)の2剤が、METex14陽性の肺癌患者に対して高い有効性を示すことから、第一選択薬としてそれぞれの保健当局から承認された。
In 2020, two MET tyrosine kinase inhibitors (hereinafter referred to as “MET-TKIs”), capmatinib (US and Japan) and tepotinib (Japan), will be used in patients with METex14-positive lung cancer. Due to its efficacy, it was approved by the respective health authorities as a first-line drug.
日本と米国における肺癌の年間死亡者数が約22万人であることを考慮すると、その約3%にあたる年間約5000人程度の人が、このMET-TKIの治療対象となりうる。これらの薬剤はEUを始めとした他の国々でも今後さらなる商品が見込まれており、より多くの患者がMET-TKIによる恩恵をうけることが予想される。
Considering that the annual death toll from lung cancer in Japan and the United States is approximately 220,000, approximately 3%, or approximately 5,000 people per year, can be treated with this MET-TKI. These drugs are expected to become more commercially available in the EU and other countries in the future, and more patients are expected to benefit from MET-TKIs.
しかしながら、これらMET-TKIによる治療では、投薬開始後しばらくは有効であるものの、約一年で薬剤に対する耐性を必ず獲得することが知られている。MET-TKIの耐性機序には、(1)MET-TKIの結合部位に変異(二次変異)が生じて耐性を示すもの、(2)MET以外のバイパス経路が活性化して耐性を示すものの大きく2種類に分けられる。これらのうち(1)は、MET-TKIの耐性機序の約35%を占めることが報告されている。(非特許文献1)
However, although these MET-TKI treatments are effective for a while after the start of medication, it is known that resistance to the drug inevitably develops after about a year. Mechanisms of resistance to MET-TKI include (1) resistance due to mutation (secondary mutation) in the binding site of MET-TKI, and (2) resistance due to activation of bypass pathways other than MET. It can be roughly divided into two types. Of these, (1) has been reported to account for approximately 35% of the resistance mechanisms of MET-TKIs. (Non-Patent Document 1)
承認を受けたカプマチニブやテポチニブは、METの活性化状態に結合するタイプI型阻害薬に分類される。そして、METex14を有する人工腫瘍細胞モデルを用いた実験により、タイプI型のMETチロシンキナーゼ阻害剤に対する耐性機構として、Asp1228(D1228:1228番目のアスパラギン酸)およびTyr1230(Y1230:1230番目のチロシン)における二次変異がしばしば起こることが報告されている(非特許文献2)。
Approved capmatinib and tepotinib are classified as type I inhibitors that bind to the activated state of MET. Then, by experiments using an artificial tumor cell model having METex14, Asp1228 (D1228: 1228th aspartic acid) and Tyr1230 (Y1230: 1230th tyrosine) as a resistance mechanism to type I MET tyrosine kinase inhibitors It has been reported that secondary mutations often occur (Non-Patent Document 2).
また、実際にタイプI型チロシンキナーゼ阻害剤の一つであるクリゾチニブ(crizotinib)がMETex14を有する肺癌患者に投与された時には、D1228とY1230において高率に耐性変異が生じることが既に報告されている(非特許文献3)。つまり、D1228とY1230における変異は、METex14陽性の肺癌患者がタイプI型のMETチロシンキナーゼ阻害剤に対して耐性を有することを示す指標として利用できる。
In addition, it has already been reported that when crizotinib, one of the type I tyrosine kinase inhibitors, is actually administered to lung cancer patients with METex14, resistance mutations occur at high rates in D1228 and Y1230. (Non-Patent Document 3). In other words, the mutations at D1228 and Y1230 can be used as indicators indicating that METex14-positive lung cancer patients have resistance to type I MET tyrosine kinase inhibitors.
上記の結果は、METex14陽性の癌細胞は、カプマチニブやテポチニブの投薬により一旦効果が得られても、一定期間が経過すると、一部の癌細胞がD1228とY1230に二次変異を獲得することを示す。そして、これらの二次変異を獲得した癌細胞は、依然として、METシグナルに依存して生存・増殖することを示している。
The above results show that even if METex14-positive cancer cells are once effective by administration of capmatinib or tepotinib, some cancer cells will acquire secondary mutations at D1228 and Y1230 after a certain period of time. show. And it shows that cancer cells that have acquired these secondary mutations still depend on MET signals to survive and proliferate.
従って、これらの腫瘍を制御するために、耐性二次変異に阻害活性を示すMET-TKIを用いることが重要である。しかし、これら耐性変異を克服しうる薬剤はin vitroレベルにおいても現時点では明らかでない。
Therefore, it is important to use MET-TKIs that exhibit inhibitory activity on secondary resistance mutations to control these tumors. However, at the present time, drugs capable of overcoming these resistance mutations have not been clarified even at the in vitro level.
本発明は、上記の課題に鑑みて想到されたものであり、カプマチニブまたはテポチニブに対する獲得耐性を克服できる新しいクラスの肺癌用MET-TKIを提供する。
The present invention has been conceived in view of the above problems, and provides a new class of MET-TKIs for lung cancer that can overcome acquired resistance to capmatinib or tepotinib.
より具体的に、本発明に係る肺癌治療薬は、
MET_exon14_Skipping変異を呈し、c-Metの1228番目と1230番目のアミノ酸がそれぞれアスパラギン酸およびチロシン以外のアミノ酸に変異している肺癌(タイプI型MET-TKIに耐性を獲得した肺癌)に対する(1)式および(2)式のいずれかの化合物を有効成分とする肺癌治療薬である。 More specifically, the therapeutic drug for lung cancer according to the present invention is
Expression (1) against lung cancer exhibiting MET_exon14_Skipping mutation and in which amino acids 1228 and 1230 of c-Met are mutated to amino acids other than aspartic acid and tyrosine (type I MET-TKI-resistant lung cancer) and (2) is a therapeutic drug for lung cancer containing as an active ingredient any one of the compounds of the formulas.
MET_exon14_Skipping変異を呈し、c-Metの1228番目と1230番目のアミノ酸がそれぞれアスパラギン酸およびチロシン以外のアミノ酸に変異している肺癌(タイプI型MET-TKIに耐性を獲得した肺癌)に対する(1)式および(2)式のいずれかの化合物を有効成分とする肺癌治療薬である。 More specifically, the therapeutic drug for lung cancer according to the present invention is
Expression (1) against lung cancer exhibiting MET_exon14_Skipping mutation and in which amino acids 1228 and 1230 of c-Met are mutated to amino acids other than aspartic acid and tyrosine (type I MET-TKI-resistant lung cancer) and (2) is a therapeutic drug for lung cancer containing as an active ingredient any one of the compounds of the formulas.
また、本発明は、Met_exon14_Skippingを有し、c-Metの1228番目と1230番目のアミノ酸がそれぞれアスパラギン酸およびチロシン以外のアミノ酸に変異している肺癌に対して(1)式および(2)式のいずれかの化合物を有効成分とする薬剤を用いる治療と言ってもよい。
In addition, the present invention provides a method for lung cancer having Met_exon14_Skipping and c-Met at amino acids 1228 and 1230 mutated to amino acids other than aspartic acid and tyrosine, respectively, in formulas (1) and (2). It may also be said that treatment using a drug containing any of the compounds as an active ingredient.
本発明に係る(1)式若しくは(2)式の化合物を有効成分とする肺癌治療薬は、METex14変異を有し、c-Metの1228番目と1230番目のアミノ酸がそれぞれアスパラギン酸およびチロシン以外のアミノ酸に変異している肺癌、すなわち、METex14が陽性であり、タイプI型のMET-TKIに対して耐性獲得した肺癌の細胞増殖抑制に奏効する。
The therapeutic drug for lung cancer containing the compound of formula (1) or formula (2) according to the present invention as an active ingredient has a METex14 mutation, and amino acids 1228 and 1230 of c-Met are other than aspartic acid and tyrosine, respectively. It is effective in suppressing the cell growth of lung cancer with amino acid mutations, that is, lung cancer that is positive for METex14 and has acquired resistance to type I MET-TKI.
また、METex14による肺癌は、ALK融合遺伝子変異による肺癌の出現頻度と同等であるとされている。ALK融合遺伝子変異に関しては、機序の異なるALKチロシンキナーゼ阻害薬(ALK-TKI)がすでに5種類も開発販売されており、最初に使用したALK-TKIに対する耐性が獲得されても、別のALK-TKIに切り替えることで耐性を克服し、予後の改善を得ることができている。したがって、METex14が陽性でありタイプI型のMET-TKIに対して耐性を獲得した肺癌を耐性克服する治療薬は、商業的にも成功する期待が高い。
In addition, lung cancer caused by METex14 is said to occur at the same frequency as lung cancer caused by ALK fusion gene mutation. Regarding the ALK fusion gene mutation, 5 types of ALK tyrosine kinase inhibitors (ALK-TKI) with different mechanisms have already been developed and marketed, and even if resistance to the first used ALK-TKI is acquired, another ALK - Switching to TKIs has overcome resistance and improved prognosis. Therefore, it is highly expected that a therapeutic agent that overcomes resistance to type I MET-TKI-positive lung cancer that is positive for METex14 will be commercially successful.
以下に本発明に係る肺癌治療薬について図面および実施例を示し説明を行う。なお、以下の説明は、本発明の一実施形態および一実施例を例示するものであり、本発明が以下の説明に限定されるものではない。以下の説明は本発明の趣旨を逸脱しない範囲で改変することができる。
The lung cancer drug according to the present invention will be described below with reference to drawings and examples. In addition, the following description illustrates one embodiment and one example of the present invention, and the present invention is not limited to the following description. The following description can be modified without departing from the spirit of the invention.
本発明に係る肺癌治療薬は、(1)式および(2)式で表される化合物を有効成分として含有する。これらの化合物は、タイプI型MET-TKIに対する耐性変異として出現が予測される二次変異を有する細胞モデルを用い、様々な作用機序を有するドラッグライブラリーから、阻害活性を示す薬剤を見つけ出す方法で見出されたものである。なお、タイプI型MET-TKIとは、チロシンキナーゼのDFG-in構造に結合することで、その阻害作用を示す薬剤である。
The therapeutic agent for lung cancer according to the present invention contains compounds represented by formulas (1) and (2) as active ingredients. These compounds are a method of finding drugs that exhibit inhibitory activity from drug libraries with various mechanisms of action using cell models that have secondary mutations that are predicted to appear as resistance mutations to type I MET-TKIs. It was found in Type I MET-TKI is a drug that exhibits inhibitory action by binding to the DFG-in structure of tyrosine kinase.
(1)式で表されるのは、物質名foretinib(特許文献1:国際公開2012/071321号)であり、(2)式で表されるのはCFP-40783(特許文献2:国際公開2015/017607号)である。これらの薬剤はタイプII型MET-TKIである。タイプII型のMET-TKIとは、チロシンキナーゼのDFG-out構造に結合することで、その阻害作用を示す薬剤である。すなわち、タイプI型MET-TKIとは、作用機序が異なり、タイプI型MET-TKIに対する耐性を克服できる可能性が高い。
Represented by the formula (1) is the substance name foretinib (Patent Document 1: International Publication No. 2012/071321), and represented by the formula (2) is CFP-40783 (Patent Document 2: International Publication 2015 /017607). These agents are type II MET-TKIs. Type II MET-TKIs are drugs that exhibit an inhibitory action by binding to the DFG-out structure of tyrosine kinases. That is, it has a different mechanism of action from type I MET-TKIs, and is likely to be able to overcome resistance to type I MET-TKIs.
これらの物質は後述する実施例に示すように、カプマチニブ、テポチニブから生じた耐性株に対して阻害効果を示した。したがって、METex14変異陽性でタイプI型MET-TKI(METチロシンキナーゼ阻害薬)に耐性獲得した肺癌に対しても耐性克服し、癌細胞増殖を抑制する効果を奏すると考えられる。
As shown in the examples below, these substances showed inhibitory effects on resistant strains generated from capmatinib and tepotinib. Therefore, it is considered that the METex14 mutation-positive lung cancer that has acquired resistance to type I MET-TKI (MET tyrosine kinase inhibitor) also has the effect of overcoming resistance and suppressing cancer cell proliferation.
言い換えると、(1)式若しくは(2)式の化合物を有効成分とする薬剤を用いて、METex14変異陽性でタイプI型MET-TKIに耐性獲得した肺癌の治療を行うことができる。
In other words, a drug containing the compound of formula (1) or formula (2) as an active ingredient can be used to treat METex14 mutation-positive lung cancer that has acquired resistance to type I MET-TKIs.
特許文献1によれば、(1)式のフォレチニブは、薬学的に許容可能な塩としてヒトに投与可能である。例えば、遊離塩基として投与できる。具体的には、フォレチニブは、例えば、1日約7.5mg、15.0mg、30.0mg、および/または45.0mgの用量で投与することができるとされる。
According to Patent Document 1, foretinib of formula (1) can be administered to humans as a pharmaceutically acceptable salt. For example, it can be administered as the free base. Specifically, it is believed that foretinib can be administered, for example, at doses of about 7.5 mg, 15.0 mg, 30.0 mg, and/or 45.0 mg daily.
また、フォレチニブは、錠剤の形態で提供されていてもよい。幾つかの場合では、錠剤は、ヒプロメロース、ラウリル硫酸ナトリウム、ラクトース一水和物、微結晶性セルロース、クロスカルメロースナトリウム、およびステアリン酸マグネシウムを含むことができる。また、幾つかの錠剤は、ヒプロメロース、二酸化チタン、ポリエチレングリコールを含んでいてもよい。さらに、錠剤は、ポリソルベート80(solysorbate 80)および黄色酸化鉄を含んでいてもよいとされる。
In addition, foretinib may be provided in tablet form. In some cases, the tablet may contain hypromellose, sodium lauryl sulfate, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. Some tablets may also contain hypromellose, titanium dioxide, polyethylene glycol. Additionally, the tablets may contain polysorbate 80 and yellow iron oxide.
また、フォレチニブ(特許文献1では、N1-{3-フルオロ-4-[(6-(メチルオキシ)-7-{[3-(4-モルホリニル)プロピル]オキシ}-4-キノリニル)オキシ]フェニル}-N1-(4-フルオロフェニル)-1,1-シクロプロパンジカルボキサミドとも呼ばれる)は、その薬学的に許容可能な塩および溶媒和物と共に、調製方法が、cMETの阻害剤として特に癌の治療に有用であるとして、2004年9月24日が国際出願日である国際出願第PCT/US2004/031523号において開示および特許請求されている。
In addition, foretinib (in Patent Document 1, N1-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4-morpholinyl)propyl]oxy}-4-quinolinyl)oxy]phenyl }-N1-(4-fluorophenyl)-1,1-cyclopropanedicarboxamide), together with pharmaceutically acceptable salts and solvates thereof, are particularly useful as inhibitors of cMET for cancer. It is disclosed and claimed in International Application No. PCT/US2004/031523 with International filing date September 24, 2004 as being useful in therapy.
その国際公開番号は、国際公開第2005/030140号であり、2005年4月7日が国際公開日である。そして、実施例25(p.193)、36(pp.202~203)、42(p.209)、43(p.209)、および44(pp.209~210)には、フォレチニブの調製方法が記載されている。
Its international publication number is International Publication No. 2005/030140, and April 7, 2005 is the international publication date. And in Examples 25 (p.193), 36 (pp.202-203), 42 (p.209), 43 (p.209), and 44 (pp.209-210), the method for preparing foretinib is described.
フォレチニブは、国際出願第PCT/US2009/064341号に記載のように調製することでき、その国際出願日は2008年11月13日であり、国際公開番号は国際公開第2010/056960号であり、国際公開日は2010年5月20日である。
Foretinib can be prepared as described in International Application No. PCT/US2009/064341, which has an international filing date of November 13, 2008 and an international publication number of WO 2010/056960; The international publication date is May 20, 2010.
フォレチニブは、国際出願第PCT/US2009/058276号に記載のように調製することでき、その国際出願日は2009年9月25日であり、国際公開番号は国際公開第2010/036831号であり、国際公開日は2010年4月1日である。
Foretinib can be prepared as described in International Application No. PCT/US2009/058276, which has an international filing date of September 25, 2009 and an international publication number of WO 2010/036831; The international publication date is April 1, 2010.
また、特許文献2によれば、CEP-40783または医薬的に許容可能なその塩は、多種多様な経口および/または非経口投与形態で投与可能である。一実施形態では、本発明の化合物は、経口で送達される。非経口投与は、注射による投与、つまり、静脈内、筋肉内、皮中、皮下、十二指腸内、または腹腔内への投与が可能である。
Also, according to Patent Document 2, CEP-40783 or a pharmaceutically acceptable salt thereof can be administered in a wide variety of oral and/or parenteral dosage forms. In one embodiment, the compounds of the invention are delivered orally. Parenteral administration can be by injection, ie, intravenous, intramuscular, intradermal, subcutaneous, intraduodenal, or intraperitoneal.
また、CEP-40783または医薬的に許容可能なその塩は、静脈内または皮下に投与される。また、CEP-40783または医薬的に許容可能なその塩は、吸引、例えば、鼻腔内に投与可能であり、さらに、経皮投与可能である。また、CEP-40783または医薬的に許容可能なその塩は、直腸送達、バッカル錠で送達、または吹送法により送達可能でもある。
CEP-40783 or a pharmaceutically acceptable salt thereof is also administered intravenously or subcutaneously. CEP-40783, or a pharmaceutically acceptable salt thereof, can also be administered by inhalation, eg intranasally, as well as transdermally. CEP-40783, or a pharmaceutically acceptable salt thereof, can also be delivered rectally, by buccal tablets, or by insufflation.
CEP-40783または医薬的に許容可能なその塩の、特定の状況に対する適切な投与量の決定は、当業者の技術範囲内である。一般的には、治療を、化合物の最適用量未満のより少ない投与量で開始する。その後、投与量を、その状況下で最適な効果に到達するまで、少しずつ量を増やして、増加させる。適宜、一日当たりの総投与量を分割し、所望ならば、一日の間に複数回に分けて投与してもよい。
Determination of the appropriate dosage of CEP-40783, or a pharmaceutically acceptable salt thereof, for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. Suitably, the total daily dosage may be divided and administered in portions during the day, if desired.
例えば、CEP-40783またはその塩を、一日当たり1回~4回投与することができる。標準的な用量は、約1mg~約1,000mg(例、約5mg~約500mg)である。
For example, CEP-40783 or a salt thereof can be administered 1 to 4 times per day. A typical dose is about 1 mg to about 1,000 mg (eg, about 5 mg to about 500 mg).
あるケースでは、標準的な用量は、約1mg~約300mg(例、約5mg~約250mg)である。さらに別の場合では、標準的な用量は、約10mg~100mgであってもよい。
In some cases, a standard dose is about 1 mg to about 300 mg (eg, about 5 mg to about 250 mg). In still other cases, a standard dose may be about 10 mg to 100 mg.
また、CEP-40783またはその塩は、体重に応じて投薬される。例えば、CEP-40783またはその塩を、約0.1mg/kg~約500mg/kg(例、約1mg/kg~約100mg/kg、または、約5mg/kg~約75mg/kg)の量で投与してもよい。また、CEP-40783またはその塩を、約10mg/kg~約55mg/kgの量で投与することもできる。CEP-40783は、任意の数の各種方法を使用して、例えば、WO2013/0074633に記載される方法を使用して、調製可能である。
In addition, CEP-40783 or its salt is administered according to body weight. For example, CEP-40783 or a salt thereof administered in an amount of about 0.1 mg/kg to about 500 mg/kg (e.g., about 1 mg/kg to about 100 mg/kg, or about 5 mg/kg to about 75 mg/kg) You may CEP-40783 or a salt thereof can also be administered in an amount of about 10 mg/kg to about 55 mg/kg. CEP-40783 can be prepared using any number of different methods, for example, using the methods described in WO2013/0074633.
フォレチニブおよびCEP-40783に関するこれらの開示は、本明細書に組み込まれてもよい。
These disclosures regarding foretinib and CEP-40783 may be incorporated herein.
タイプI型MET-TKIに対する耐性変異として出現が予測される二次変異(D1228A/E/G/N/Y/VとY1230C/D/H/N/S)を有するBa/F3細胞モデルを遺伝子組み換え技術を用いて作製した。
Gene Ba/F3 cell model with secondary mutations (D1228A/E/G/N/Y/V and Y1230C/D/H/N/S) that are predicted to appear as resistance mutations to type I MET-TKI Produced using recombinant technology.
<MET exon14 skippign変異を有するBa/F3細胞の樹立>
Ba/F3細胞は、マウス由来のproB細胞であり、通常は、その生存のためには外来からのインターロイキン3(IL3)を必要とする。しかし、ドライバー遺伝子変異を、レトロウイルス等を用いて外来導入すると、トランスフォームしてIL3がなくとも、導入したドライバー遺伝子変異のみに依存して生存増殖を示すことが知られている。 <Establishment of Ba/F3 cells with MET exon14 skippign mutation>
Ba/F3 cells are mouse-derived proB cells that normally require exogenous interleukin 3 (IL3) for their survival. However, it is known that when a driver gene mutation is exogenously introduced using a retrovirus or the like, cells survive and proliferate depending only on the introduced driver gene mutation, even without IL3 after transformation.
Ba/F3細胞は、マウス由来のproB細胞であり、通常は、その生存のためには外来からのインターロイキン3(IL3)を必要とする。しかし、ドライバー遺伝子変異を、レトロウイルス等を用いて外来導入すると、トランスフォームしてIL3がなくとも、導入したドライバー遺伝子変異のみに依存して生存増殖を示すことが知られている。 <Establishment of Ba/F3 cells with MET exon14 skippign mutation>
Ba/F3 cells are mouse-derived proB cells that normally require exogenous interleukin 3 (IL3) for their survival. However, it is known that when a driver gene mutation is exogenously introduced using a retrovirus or the like, cells survive and proliferate depending only on the introduced driver gene mutation, even without IL3 after transformation.
まず、MET exon14 skipping変異を有する遺伝子組み換えレトロウイルスを作成し、Ba/F3細胞に感染させた。
First, a genetically modified retrovirus with a MET exon14 skipping mutation was created and infected with Ba/F3 cells.
IL3を除去して、MET exon 14 skipping遺伝子変異のみに依存して生存増殖を示すBa/F3細胞を樹立した。これをMETex14-Ba/F3細胞と呼ぶ。
By removing IL3, Ba/F3 cells were established that showed survival and proliferation depending only on the MET exon 14 skipping gene mutation. These are called METex14-Ba/F3 cells.
<capmatinib, tepotinibに対する耐性を有するBa/F3細胞の樹立>
次にタイプI型MET-TKIに耐性を有する耐性株を作製した。上記で樹立したMETex14-Ba/F3細胞をENU(エチルニトロソウレア)に24時間暴露した。 <Establishment of Ba/F3 cells resistant to capmatinib and tepotinib>
Next, a resistant strain having resistance to type I MET-TKI was constructed. METex14-Ba/F3 cells established above were exposed to ENU (ethylnitrosourea) for 24 hours.
次にタイプI型MET-TKIに耐性を有する耐性株を作製した。上記で樹立したMETex14-Ba/F3細胞をENU(エチルニトロソウレア)に24時間暴露した。 <Establishment of Ba/F3 cells resistant to capmatinib and tepotinib>
Next, a resistant strain having resistance to type I MET-TKI was constructed. METex14-Ba/F3 cells established above were exposed to ENU (ethylnitrosourea) for 24 hours.
96 well plate上でカプマチニブ若しくはテポチニブをそれぞれ投与し、その存在下で約3週間培養することで、METのチロシンキナーゼ結合部位に変異を起こし、耐性となった細胞株を作製した。
By administering capmatinib or tepotinib on a 96-well plate and culturing in its presence for about 3 weeks, a mutation was induced in the tyrosine kinase binding site of MET to prepare a resistant cell line.
得られた耐性株のキナーゼ領域をサンガーシークエンス法で解析し、二次変異の種類を調べて、各変異を有する細胞を樹立した。この結果、METex14-Ba/F3細胞におけるc-Metの1228番目のアスパラギン酸(D)が、アラニン(A)、グルタミン酸(E)、グリシン(G)、ヒスチジン(H)、アスパラギン(N)、バリン(V)、チロシン(Y)に変異したMETex14-Ba/F3細胞を得た。それぞれの細胞株を単にD1228A、D1228E、D1228G、D1228H、D1228N、D1228V、D1228Yと呼ぶ。
The kinase regions of the obtained resistant strains were analyzed by the Sanger sequencing method, the types of secondary mutations were investigated, and cells with each mutation were established. As a result, aspartic acid (D) at position 1228 of c-Met in METex14-Ba/F3 cells is replaced by alanine (A), glutamic acid (E), glycine (G), histidine (H), asparagine (N), and valine. (V), METex14-Ba/F3 cells mutated to tyrosine (Y) were obtained. The respective cell lines are simply called D1228A, D1228E, D1228G, D1228H, D1228N, D1228V, D1228Y.
また、METex14-Ba/F3細胞におけるc-Metの1230番目のチロシン(Y)が、システイン(C)、アスパラギン酸(D)、ヒスチジン(H)、アスパラギン(N)、セリン(S)に変異したMETex14-Ba/F3細胞も得た。それぞれの細胞株を単にY1230C、Y1230D、Y1230H、Y1230N、Y1230Sと呼ぶ。また、D1228番目およびY1230番目が変異したこれらの細胞を「サンプル細胞」と呼ぶ。また、これは「METex14-Ba/F3耐性細胞」と呼んでもよい。
In addition, tyrosine (Y) at position 1230 of c-Met in METex14-Ba/F3 cells was mutated to cysteine (C), aspartic acid (D), histidine (H), asparagine (N), and serine (S). METex14-Ba/F3 cells were also obtained. Each cell line is simply called Y1230C, Y1230D, Y1230H, Y1230N, Y1230S. In addition, these cells with mutations at D1228th and Y1230th are referred to as "sample cells". It may also be referred to as "METex14-Ba/F3 resistant cells".
これらの細胞は、タイプI型MET-TKIに対して耐性を有するモデル細胞である。また、c-Metの1228番目と1230番目のアミノ酸がアスパラギン酸(D)とチロシン(Y)以外のアミノ酸に変異した細胞であるといってもよい。さらに、METex14変異を有し、カプマチニブ若しくはテポチニブに対して耐性を獲得したモデル細胞である。
These cells are model cells that are resistant to type I MET-TKI. Also, it can be said that the cell is a cell in which the 1228th and 1230th amino acids of c-Met are mutated to amino acids other than aspartic acid (D) and tyrosine (Y). Furthermore, it is a model cell that has a METex14 mutation and has acquired resistance to capmatinib or tepotinib.
これらのモデル細胞に対してドラッグライブラリーに登録された作用機序が様々な薬剤300種(以下「サンプル薬剤」と呼ぶ。)を投与し、耐性を克服してMET-TKIとしての効果を奏する薬剤を探した。具体的な手順は以下の通りとした。
To these model cells, 300 drugs with various mechanisms of action registered in the drug library (hereinafter referred to as "sample drugs") are administered to overcome resistance and produce effects as MET-TKIs. I searched for drugs. The specific procedure was as follows.
1日目に通常のBa/F3細胞、METex14-Ba/F3細胞(二次変異なし)、METex14-Ba/F3耐性細胞(二次変異有)のうち、D1228AとD1228Yの2種類、計4種類のBa/F3細胞を96well plateに3000個ずつ播種した。なお、通常のBa-F3細胞にはIL3も添加した。
On the first day, normal Ba / F3 cells, METex14-Ba / F3 cells (no secondary mutation), METex14-Ba / F3 resistant cells (with secondary mutation), 2 types of D1228A and D1228Y, total 4 types 3,000 Ba/F3 cells were seeded in each 96-well plate. IL3 was also added to normal Ba-F3 cells.
2日目に300種類の薬剤を全て100nMの濃度で投与した。また、plate毎に1wellは、DMSOをコントロールとして投与した。このwellを「コントロールウェル」と呼ぶ。
On the second day, all 300 drugs were administered at a concentration of 100 nM. In addition, DMSO was administered to 1 well per plate as a control. This well is called a "control well".
5日目(薬剤投与72h後)にcell counting kit8を各wellに10μlずつ投与し、3時間後にプレートリーダーを用いて450nMの吸光度を直接測定することにより、生細胞数を測定した。
On day 5 (72 hours after drug administration), 10 μl of cell counting kit 8 was administered to each well, and 3 hours later, the absorbance at 450 nM was directly measured using a plate reader to measure the number of viable cells.
METex14-Ba/F3細胞、D1228A、D1228Y(これら2種はいずれもMETex14-Ba/F3耐性細胞)の3種類の細胞においてDMSOを投与したコントロールウェルと比較して、生存率が50%以下となったものを候補薬剤として選定した。通常のBa/F3細胞にも効果を示した薬剤に関しては、MET signalに特異的に阻害効果を示したものではないと判断して除外した。IC50および生存率は以下のようにして求めた。
In three types of cells, METex14-Ba/F3 cells, D1228A, and D1228Y (both of which are METex14-Ba/F3-resistant cells), the survival rate was 50% or less compared to DMSO-administered control wells. were selected as candidate drugs. Drugs that showed effects also on normal Ba/F3 cells were excluded, judging that they did not show inhibitory effects specifically on MET signal. IC50 and viability were determined as follows.
各サンプル薬剤における生存割合は、コントロールウェルの生細胞数に対する各ウェルの生細胞数の割合(百分率)として算出し、サンプル薬剤濃度に対する生存率の曲線を作成した。グラフの一例を図1に示す。
The survival rate for each sample drug was calculated as the ratio (percentage) of the number of viable cells in each well to the number of viable cells in the control wells, and a curve of viability versus sample drug concentration was created. An example of the graph is shown in FIG.
図1は、c-Metの1228番目のアスパラギン酸(D)がアスパラギン(N)に変異したサンプル細胞に対して、カボザンチニブを投与した場合の薬剤濃度(nM)-細胞生存率(%)のグラフである。グラフでは「METex14+D1228N-Ba/F3細胞 vs cabozantinib」と記した。横軸はサンプル薬剤濃度(nM)であり、縦軸は生存率(%)である。サンプル薬剤濃度がおよそ37.04nMで、細胞生存率が50%であることがわかる。このようなグラフを元に、生存割合が50%となる薬剤濃度(IC50)をサンプル薬剤毎に算出した。表1に、二次変異に対する耐性を克服できたサンプル薬剤とできなかった薬剤の結果例を示す。
Figure 1 is a graph of drug concentration (nM) - cell viability (%) when cabozantinib was administered to sample cells in which aspartic acid (D) at position 1228 of c-Met was mutated to asparagine (N). is. In the graph, "METex14+D1228N-Ba/F3 cells vs. cabozantinib" was written. The horizontal axis is sample drug concentration (nM) and the vertical axis is viability (%). It can be seen that the sample drug concentration is approximately 37.04 nM and the cell viability is 50%. Based on such a graph, the drug concentration (IC50) at which the survival rate becomes 50% was calculated for each sample drug. Table 1 shows example results of sample drugs that were able to overcome resistance to secondary mutations and drugs that were not.
表1を参照して、結論からいうとCEP-40783と、フォレチニブの2薬剤だけが、二次変異として想定される全ての変異に対して耐性を克服できた。
With reference to Table 1, the conclusion is that only two drugs, CEP-40783 and foretinib, were able to overcome resistance to all mutations assumed to be secondary mutations.
表1を参照して、左端にはMETex14の親株(METex14-Ba/F3細胞)と、1228番目のアスパラギン酸(D)が、アラニン(A)、グルタミン酸(E)、グリシン(G)、ヒスチジン(H)、アスパラギン(N)、バリン(V)、チロシン(Y)へ変異したMETex14-Ba/F3変異細胞および、1230番目のチロシン(Y)が、システイン(C)、アスパラギン酸(D)、ヒスチジン(H)、アスパラギン(N)、セリン(S)へ変異したMETex14-Ba/F3変異細胞を表している。
With reference to Table 1, on the left end of METex14 parent strain (METex14-Ba/F3 cells), 1228th aspartic acid (D), alanine (A), glutamic acid (E), glycine (G), histidine ( H), METex14-Ba/F3 mutant cells mutated to asparagine (N), valine (V), and tyrosine (Y), and tyrosine (Y) at position 1230 is cysteine (C), aspartic acid (D), histidine (H), METex14-Ba/F3 mutant cells mutated to asparagine (N), serine (S).
それぞれの細胞株は、D1228A、D1228E、D1228G、D1228H、D1228N、D1228V、D1228Y、Y1230C、Y1230D、Y1230H、Y1230N、Y1230Sとも呼ぶ点をすでに述べた。
As already mentioned, each cell line is also called D1228A, D1228E, D1228G, D1228H, D1228N, D1228V, D1228Y, Y1230C, Y1230D, Y1230H, Y1230N, Y1230S.
第1行目および第2行目は、タイプI型のMET-TKIとしてカプマチニブ(capmatinib)とテポチニブ(tepotinib)を投与した場合のIC50濃度を示している。また、第3行目、第4行目は、タイプII型のMET-TKIとしてCEP-40783とフォレチニブ(foretinib)を投与した結果を表している。また、第4行目と第五行目は、TypeIIのMET-TKIとしてカボザンチニブ(cabozantinib)とメレスチニブ(merestinib)の結果を示している。
The first and second rows show the IC50 concentrations when capmatinib and tepotinib are administered as type I MET-TKIs. The third and fourth lines show the results of administering CEP-40783 and foretinib as type II MET-TKIs. The fourth and fifth rows show the results of cabozantinib and merestinib as Type II MET-TKIs.
タイプI型MET-TKI(カプマチニブとテポチニブ)は、METex14の親株に対しては、IC50が0.6nMおよび3.0nMであり、有効にc-Met阻害効を奏していた。
The type I MET-TKIs (capmatinib and tepotinib) had an IC50 of 0.6 nM and 3.0 nM against the parent strain of METex14, demonstrating an effective c-Met inhibitory effect.
しかし、二次変異を有したMETex14-Ba/F3変異細胞に対しては、どの二次変異に対してもIC50が100nM以上となった。特にテポチニブはいずれのMETex14-Ba/F3変異細胞に対してもIC50が1000nMより高くなった。すなわち、これらのタイプI型のMET―TKIは、二次変異細胞に対しては、阻害効果を奏しなかった。言い換えると、二次変異したMETex14-Ba/F3変異細胞は、タイプI型のこれらのサンプル薬剤に対して耐性を獲得していたと言える。
However, for METex14-Ba/F3 mutant cells with secondary mutations, the IC50 was 100 nM or more for any secondary mutation. In particular, tepotinib had an IC50 higher than 1000 nM against all METex14-Ba/F3 mutant cells. That is, these type I MET-TKIs had no inhibitory effect on secondary mutant cells. In other words, the secondary mutated METex14-Ba/F3 mutant cells acquired resistance to these sample agents of type I type.
タイプII型MET-TKIであるカボザンチニブとメレスチニブは、1230番目のチロシン(Y)が変異した場合は、いずれも30nM以下とIC50は低かった。すなわち、耐性を克服して、c-Met阻害効効果を発揮していると言えた。しかし、1228番目のアスパラギン酸(D)が変異した場合は、IC50が30nMより大きくなる場合が多かった。
The type II MET-TKIs cabozantinib and merestinib had a low IC50 of 30 nM or less when the 1230th tyrosine (Y) was mutated. In other words, it could be said that the c-Met inhibitory effect was exhibited by overcoming the resistance. However, when the 1228th aspartic acid (D) was mutated, the IC50 was often greater than 30 nM.
一方、タイプII型MET-TKIであるCEP-40783とフォレチニブは、1228番目および1230番目のどちらの変異に対しても、IC50は30nM以下であり、なおかつほとんどの場合10nM以下と大変優れた結果を示した。つまり、これら2つの薬剤は、METex14が発現し、なおかつ1228番目と1230番目のアミノ酸に変異を生じた細胞に対して、耐性を克服し、METチロシンキナーゼ阻害効を奏すると結論できた。
On the other hand, CEP-40783 and foretinib, which are type II MET-TKIs, for both the 1228th and 1230th mutations, the IC50 is 30 nM or less, and in most cases it is 10 nM or less. Indicated. In other words, it was concluded that these two drugs overcome the resistance to cells in which METex14 is expressed and in which the 1228th and 1230th amino acids are mutated, and exerts an inhibitory effect on MET tyrosine kinase.
以上のことから、これら2つのサンプル薬剤は、タイプI型のMET―TKIが耐性によって効果を奏しなくなった後に、その耐性を克服して引き続き使用することが可能な薬剤として利用できると言える。
From the above, it can be said that these two sample drugs can be used as drugs that can be used continuously after overcoming the resistance after the type I MET-TKI has become ineffective due to resistance.
また、いいかえると、METex14が発現し、なおかつ1228番目と1230番目のアミノ酸に変異を生じた肺癌(タイプI型MET-TKIに耐性を獲得した肺癌)に対して、これらの薬剤を用いた治療が可能であると言ってもよい。
In other words, treatment using these drugs is effective against lung cancer in which METex14 is expressed and in which amino acids at positions 1228 and 1230 are mutated (type I type MET-TKI-resistant lung cancer). It can be said that it is possible.
本発明に係る肺癌用治療薬は、METex14が発現し、なおかつ1228番目と1230番目のアミノ酸に変異を生じた肺癌(タイプI型MET-TKIに耐性を獲得した肺癌)に対して、有効に効果を奏し、in vivoにおいても癌細胞の増殖を抑制する効果を期待できる。
The therapeutic drug for lung cancer according to the present invention is effective against lung cancer in which METex14 is expressed and amino acids 1228 and 1230 are mutated (type I MET-TKI-resistant lung cancer). and can be expected to have the effect of suppressing the proliferation of cancer cells in vivo.
The therapeutic drug for lung cancer according to the present invention is effective against lung cancer in which METex14 is expressed and amino acids 1228 and 1230 are mutated (type I MET-TKI-resistant lung cancer). and can be expected to have the effect of suppressing the proliferation of cancer cells in vivo.
Claims (1)
- MET_exon14_Skipping変異を有し、c-Metの1228番目と1230番目のアミノ酸がそれぞれアスパラギン酸およびチロシン以外のアミノ酸に変異している肺癌に対する(1)式および(2)式のいずれかの化合物を有効成分とする肺癌治療薬。
Lung cancer with MET_exon14_Skipping mutation, amino acids 1228 and 1230 of c-Met are mutated to amino acids other than aspartic acid and tyrosine, respectively, the compound of formula (1) or (2) as an active ingredient and lung cancer drug.
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JP2023501971A JP7633724B2 (en) | 2021-02-26 | 2021-02-26 | Drug for lung cancer that has acquired resistance to type I anticancer drugs |
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Citations (1)
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JP2016527274A (en) * | 2013-08-02 | 2016-09-08 | イグナイタ インコーポレイテッド | Methods for treating various cancers using AXL / cMET inhibitors alone or in combination with other drugs |
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JP2016527274A (en) * | 2013-08-02 | 2016-09-08 | イグナイタ インコーポレイテッド | Methods for treating various cancers using AXL / cMET inhibitors alone or in combination with other drugs |
Non-Patent Citations (4)
Title |
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COLLIE, G. W. ET AL.: "Structural and molecular insight into resistance mechanisms of first generation cMET inhibitors", ACS MEDICINAL CHEMISTRY LETTERS, vol. 10, no. 9, 2019, pages 1322 - 1327, XP055965269 * |
FUJINO, TOSHIO ET AL.: "Sensitivity and resistance of MET exon 14 mutations in lung cancer to eight MET tyrosine kinase inhibitors In vitro", JOURNAL OF THORACIC ONCOLOGY, vol. 14, no. 10, pages 1753 - 1765, XP055965291 * |
LIU, L. ET AL.: "Abstract A238: The effects of foretinib on MET phosphorylation, gene expression, cell proliferation and tumor growth in MET- amplified tumor cells in vitro and in vivo", MOLECULAR CANCER THERAPEUTICS, vol. 8, no. 12, 2009 * |
WANG, R. P. ET AL.: "Abstract LB-095: Type II tyrosine kinase inhibitors overcome novel acquired crizotinib-resistant MET mutations identified in gastric cancer patient", CANCER RESEARCH, vol. 78, no. 13, 2018, XP009534179 * |
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