[go: up one dir, main page]
More Web Proxy on the site http://driver.im/ Skip to main content

Advertisement

Springer Nature Link
Log in

Rational Design, synthesis and biological evaluation of novel triazole derivatives as potent and selective PRMT5 inhibitors with antitumor activity

  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

    We’re sorry, something doesn't seem to be working properly.

    Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Abstract

Protein arginine methyltransferase 5 (PRMT5) is responsible for the mono-methylation and symmetric dimethylation of arginine, and its expression level and methyl transferring activity have been demonstrated to have a close relationship with tumorigenesis, development and poor clinical outcomes of human cancers. Two PRMT5 small molecule inhibitors (GSK3326595 and JNJ-64619178) have been put forward into clinical trials. Here, we describe the design, synthesis and biological evaluation of a series of novel, potent and selective PRMT5 inhibitors with antiproliferative activity against Z-138 mantle cell lymphoma cell line. Among them, compound C_4 exhibited the highest potency with enzymatic and cellular level IC50 values of 0.72 and 2.6 μM, respectively, and displayed more than 270-fold selectivity toward PRMT5 over several other isoenzymes (PRMT1, PRMT4 and PRMT6). Besides, C_4 demonstrated obvious cell apoptotic effect while reduced the cellular symmetric arginine dimethylation levels of SmD3 protein. The potency, small size, and synthetic accessibility of this compound class provide promising hit scaffold for medicinal chemists to further explore this series of PRMT5 inhibitors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
£29.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (United Kingdom)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Scheme 1
Scheme 2
Scheme 3
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Blanc RS, Richard S (2017) Arginine methylation: the coming of age. Mol Cell 65(1):8–24. https://doi.org/10.1016/j.molcel.2016.11.003

    Article  CAS  PubMed  Google Scholar 

  2. Cheung N, Chan LC, Thompson A, Cleary ML, So CW (2007) Protein arginine-methyltransferase-dependent oncogenesis. Nat Cell Biol 9(10):1208–1215. https://doi.org/10.1038/ncb1642

    Article  CAS  PubMed  Google Scholar 

  3. Copeland RA (2013) Molecular pathways: protein methyltransferases in cancer. Clin Cancer Res 19(23):6344–6350. https://doi.org/10.1158/1078-0432.CCR-13-0223

    Article  CAS  PubMed  Google Scholar 

  4. Kim MS, Pinto SM, Getnet D, Nirujogi RS, Manda SS, Chaerkady R, Madugundu AK, Kelkar DS, Isserlin R, Jain S, Thomas JK, Muthusamy B, Leal-Rojas P, Kumar P, Sahasrabuddhe NA, Balakrishnan L, Advani J, George B, Renuse S, Selvan LD, Patil AH, Nanjappa V, Radhakrishnan A, Prasad S, Subbannayya T, Raju R, Kumar M, Sreenivasamurthy SK, Marimuthu A, Sathe GJ, Chavan S, Datta KK, Subbannayya Y, Sahu A, Yelamanchi SD, Jayaram S, Rajagopalan P, Sharma J, Murthy KR, Syed N, Goel R, Khan AA, Ahmad S, Dey G, Mudgal K, Chatterjee A, Huang TC, Zhong J, Wu X, Shaw PG, Freed D, Zahari MS, Mukherjee KK, Shankar S, Mahadevan A, Lam H, Mitchell CJ, Shankar SK, Satishchandra P, Schroeder JT, Sirdeshmukh R, Maitra A, Leach SD, Drake CG, Halushka MK, Prasad TS, Hruban RH, Kerr CL, Bader GD, Iacobuzio-Donahue CA, Gowda H, Pandey A (2014) A draft map of the human proteome. Nature 509(7502):575–581. https://doi.org/10.1038/nature13302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chen H, Lorton B, Gupta V, Shechter D (2017) A TGFbeta-PRMT5-MEP50 axis regulates cancer cell invasion through histone H3 and H4 arginine methylation coupled transcriptional activation and repression. Oncogene 36(3):373–386. https://doi.org/10.1038/onc.2016.205

    Article  CAS  PubMed  Google Scholar 

  6. Bezzi M, Teo SX, Muller J, Mok WC, Sahu SK, Vardy LA, Bonday ZQ, Guccione E (2013) Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery. Genes Dev 27(17):1903–1916. https://doi.org/10.1101/gad.219899.113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Jansson M, Durant ST, Cho EC, Sheahan S, Edelmann M, Kessler B, La Thangue NB (2008) Arginine methylation regulates the p53 response. Nat Cell Biol 10(12):1431–1439. https://doi.org/10.1038/ncb1802

    Article  CAS  PubMed  Google Scholar 

  8. Dacwag CS, Ohkawa Y, Pal S, Sif S, Imbalzano AN (2007) The protein arginine methyltransferase Prmt5 is required for myogenesis because it facilitates ATP-dependent chromatin remodeling. Mol Cell Biol 27(1):384–394. https://doi.org/10.1128/MCB.01528-06

    Article  CAS  PubMed  Google Scholar 

  9. Karkhanis V, Hu YJ, Baiocchi RA, Imbalzano AN, Sif S (2011) Versatility of PRMT5-induced methylation in growth control and development. Trends Biochem Sci 36(12):633–641. https://doi.org/10.1016/j.tibs.2011.09.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Brahms H, Meheus L, de Brabandere V, Fischer U, Luhrmann R (2001) Symmetrical dimethylation of arginine residues in spliceosomal Sm protein B/B’ and the Sm-like protein LSm4, and their interaction with the SMN protein. RNA 7(11):1531–1542

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chung J, Karkhanis V, Tae S, Yan F, Smith P, Ayers LW, Agostinelli C, Pileri S, Denis GV, Baiocchi RA, Sif S (2013) Protein arginine methyltransferase 5 (PRMT5) inhibition induces lymphoma cell death through reactivation of the retinoblastoma tumor suppressor pathway and polycomb repressor complex 2 (PRC2) silencing. J Biol Chem 288(49):35534–35547. https://doi.org/10.1074/jbc.M113.510669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wang L, Pal S, Sif S (2008) Protein arginine methyltransferase 5 suppresses the transcription of the RB family of tumor suppressors in leukemia and lymphoma cells. Mol Cell Biol 28(20):6262–6277. https://doi.org/10.1128/MCB.00923-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Pal S, Baiocchi RA, Byrd JC, Grever MR, Jacob ST, Sif S (2007) Low levels of miR-92b/96 induce PRMT5 translation and H3R8/H4R3 methylation in mantle cell lymphoma. EMBO J 26(15):3558–3569. https://doi.org/10.1038/sj.emboj.7601794

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Powers MA, Fay MM, Factor RE, Welm AL, Ullman KS (2011) Protein arginine methyltransferase 5 accelerates tumor growth by arginine methylation of the tumor suppressor programmed cell death 4. Cancer Res 71(16):5579–5587. https://doi.org/10.1158/0008-5472.CAN-11-0458

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wei TY, Juan CC, Hisa JY, Su LJ, Lee YC, Chou HY, Chen JM, Wu YC, Chiu SC, Hsu CP, Liu KL, Yu CT (2012) Protein arginine methyltransferase 5 is a potential oncoprotein that upregulates G1 cyclins/cyclin-dependent kinases and the phosphoinositide 3-kinase/AKT signaling cascade. Cancer Sci 103(9):1640–1650. https://doi.org/10.1111/j.1349-7006.2012.02367.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cho EC, Zheng S, Munro S, Liu G, Carr SM, Moehlenbrink J, Lu YC, Stimson L, Khan O, Konietzny R, McGouran J, Coutts AS, Kessler B, Kerr DJ, Thangue NB (2012) Arginine methylation controls growth regulation by E2F-1. EMBO J 31(7):1785–1797. https://doi.org/10.1038/emboj.2012.17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Jiang H, Zhu Y, Zhou Z, Xu J, Jin S, Xu K, Zhang H, Sun Q, Wang J, Xu J (2018) PRMT5 promotes cell proliferation by inhibiting BTG2 expression via the ERK signaling pathway in hepatocellular carcinoma. Cancer Med 7(3):869–882. https://doi.org/10.1002/cam4.1360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gulla A, Hideshima T, Bianchi G, Fulciniti M, Kemal Samur M, Qi J, Tai YT, Harada T, Morelli E, Amodio N, Carrasco R, Tagliaferri P, Munshi NC, Tassone P, Anderson KC (2018) Protein arginine methyltransferase 5 has prognostic relevance and is a druggable target in multiple myeloma. Leukemia 32(4):996–1002. https://doi.org/10.1038/leu.2017.334

    Article  CAS  PubMed  Google Scholar 

  19. Yan F, Alinari L, Lustberg ME, Martin LK, Cordero-Nieves HM, Banasavadi-Siddegowda Y, Virk S, Barnholtz-Sloan J, Bell EH, Wojton J, Jacob NK, Chakravarti A, Nowicki MO, Wu X, Lapalombella R, Datta J, Yu B, Gordon K, Haseley A, Patton JT, Smith PL, Ryu J, Zhang X, Mo X, Marcucci G, Nuovo G, Kwon CH, Byrd JC, Chiocca EA, Li C, Sif S, Jacob S, Lawler S, Kaur B, Baiocchi RA (2014) Genetic validation of the protein arginine methyltransferase PRMT5 as a candidate therapeutic target in glioblastoma. Cancer Res 74(6):1752–1765. https://doi.org/10.1158/0008-5472.CAN-13-0884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Alinari L, Mahasenan KV, Yan F, Karkhanis V, Chung JH, Smith EM, Quinion C, Smith PL, Kim L, Patton JT, Lapalombella R, Yu B, Wu Y, Roy S, De Leo A, Pileri S, Agostinelli C, Ayers L, Bradner JE, Chen-Kiang S, Elemento O, Motiwala T, Majumder S, Byrd JC, Jacob S, Sif S, Li C, Baiocchi RA (2015) Selective inhibition of protein arginine methyltransferase 5 blocks initiation and maintenance of B-cell transformation. Blood 125(16):2530–2543. https://doi.org/10.1182/blood-2014-12-619783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chiang K, Zielinska AE, Shaaban AM, Sanchez-Bailon MP, Jarrold J, Clarke TL, Zhang J, Francis A, Jones LJ, Smith S, Barbash O, Guccione E, Farnie G, Smalley MJ, Davies CC (2017) PRMT5 is a critical regulator of breast cancer stem cell function via histone methylation and FOXP1 expression. Cell Rep 21(12):3498–3513. https://doi.org/10.1016/j.celrep.2017.11.096

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Tamiya H, Kim H, Klymenko O, Kim H, Feng Y, Zhang T, Han JY, Murao A, Snipas SJ, Jilaveanu L, Brown K, Kluger H, Zhang H, Iwai K, Ronai ZA (2018) SHARPIN-mediated regulation of protein arginine methyltransferase 5 controls melanoma growth. J Clin Investig 128(1):517–530. https://doi.org/10.1172/JCI95410

    Article  PubMed  Google Scholar 

  23. Chan-Penebre E, Kuplast KG, Majer CR, Boriack-Sjodin PA, Wigle TJ, Johnston LD, Rioux N, Munchhof MJ, Jin L, Jacques SL, West KA, Lingaraj T, Stickland K, Ribich SA, Raimondi A, Scott MP, Waters NJ, Pollock RM, Smith JJ, Barbash O, Pappalardi M, Ho TF, Nurse K, Oza KP, Gallagher KT, Kruger R, Moyer MP, Copeland RA, Chesworth R, Duncan KW (2015) A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. Nat Chem Biol 11(6):432–437. https://doi.org/10.1038/nchembio.1810

    Article  CAS  PubMed  Google Scholar 

  24. Kaushik S, Liu F, Veazey KJ, Gao G, Das P, Neves LF, Lin K, Zhong Y, Lu Y, Giuliani V, Bedford MT, Nimer SD, Santos MA (2018) Genetic deletion or small-molecule inhibition of the arginine methyltransferase PRMT5 exhibit anti-tumoral activity in mouse models of MLL-rearranged AML. Leukemia 32(2):499–509. https://doi.org/10.1038/leu.2017.206

    Article  CAS  PubMed  Google Scholar 

  25. Smil D, Eram MS, Li F, Kennedy S, Szewczyk MM, Brown PJ, Barsyte-Lovejoy D, Arrowsmith CH, Vedadi M, Schapira M (2015) Discovery of a dual PRMT5-PRMT7 inhibitor. ACS Med Chem Lett 6(4):408–412. https://doi.org/10.1021/ml500467h

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Duncan KW, Rioux N, Boriack-Sjodin PA, Munchhof MJ, Reiter LA, Majer CR, Jin L, Johnston LD, Chan-Penebre E, Kuplast KG, Porter Scott M, Pollock RM, Waters NJ, Smith JJ, Moyer MP, Copeland RA, Chesworth R (2016) Structure and property guided design in the identification of PRMT5 tool compound EPZ015666. ACS Med Chem Lett 7(2):162–166. https://doi.org/10.1021/acsmedchemlett.5b00380

    Article  CAS  PubMed  Google Scholar 

  27. Ji S, Ma S, Wang WJ, Huang SZ, Wang TQ, Xiang R, Hu YG, Chen Q, Li LL, Yang SY (2017) Discovery of selective protein arginine methyltransferase 5 inhibitors and biological evaluations. Chem Biol Drug Des 89(4):585–598. https://doi.org/10.1111/cbdd.12881

    Article  CAS  PubMed  Google Scholar 

  28. Kong GM, Yu M, Gu Z, Chen Z, Xu RM, O’Bryant D, Wang Z (2017) Selective small-chemical inhibitors of protein arginine methyltransferase 5 with anti-lung cancer activity. PLoS ONE 12(8):e0181601. https://doi.org/10.1371/journal.pone.0181601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Mao R, Shao J, Zhu K, Zhang Y, Ding H, Zhang C, Shi Z, Jiang H, Sun D, Duan W, Luo C (2017) Potent, selective, and cell active protein arginine methyltransferase 5 (PRMT5) inhibitor developed by structure-based virtual screening and hit optimization. J Med Chem 60(14):6289–6304. https://doi.org/10.1021/acs.jmedchem.7b00587

    Article  CAS  PubMed  Google Scholar 

  30. Prabhu L, Chen L, Wei H, Demir O, Safa A, Zeng L, Amaro RE, O’Neil BH, Zhang ZY, Lu T (2017) Development of an AlphaLISA high throughput technique to screen for small molecule inhibitors targeting protein arginine methyltransferases. Mol BioSyst 13(12):2509–2520. https://doi.org/10.1039/c7mb00391a

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bonday ZQ, Cortez GS, Grogan MJ, Antonysamy S, Weichert K, Bocchinfuso WP, Li F, Kennedy S, Li B, Mader MM, Arrowsmith CH, Brown PJ, Eram MS, Szewczyk MM, Barsyte-Lovejoy D, Vedadi M, Guccione E, Campbell RM (2018) LLY-283, a potent and selective inhibitor of arginine methyltransferase 5, PRMT5, with antitumor activity. ACS Med Chem Lett 9(7):612–617. https://doi.org/10.1021/acsmedchemlett.8b00014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ye F, Zhang W, Ye X, Jin J, Lv Z, Luo C (2018) Identification of selective, cell active inhibitors of protein arginine methyltransferase 5 through structure-based virtual screening and biological assays. J Chem Inf Model 58(5):1066–1073. https://doi.org/10.1021/acs.jcim.8b00050

    Article  CAS  PubMed  Google Scholar 

  33. Zhu K, Tao H, Song JL, Jin L, Zhang Y, Liu J, Chen Z, Jiang CS, Luo C, Zhang H (2018) Identification of 5-benzylidene-2-phenylthiazolones as potent PRMT5 inhibitors by virtual screening, structural optimization and biological evaluations. Bioorg Chem 81:289–298. https://doi.org/10.1016/j.bioorg.2018.08.021

    Article  CAS  PubMed  Google Scholar 

  34. Antonysamy S, Bonday Z, Campbell RM, Doyle B, Druzina Z, Gheyi T, Han B, Jungheim LN, Qian Y, Rauch C, Russell M, Sauder JM, Wasserman SR, Weichert K, Willard FS, Zhang A, Emtage S (2012) Crystal structure of the human PRMT5:MEP50 complex. Proc Natl Acad Sci USA 109(44):17960–17965. https://doi.org/10.1073/pnas.1209814109

    Article  PubMed  PubMed Central  Google Scholar 

  35. Gerhart SV, Kellner WA, Thompson C, Pappalardi MB, Zhang XP, Montes de Oca R, Penebre E, Duncan K, Boriack-Sjodin A, Le B, Majer C, McCabe MT, Carpenter C, Johnson N, Kruger RG, Barbash O (2018) Activation of the p53-MDM4 regulatory axis defines the anti-tumour response to PRMT5 inhibition through its role in regulating cellular splicing. Sci Rep 8(1):9711. https://doi.org/10.1038/s41598-018-28002-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Brehmer D, Wu T, Mannens G, Beke L, Vinken P, Gaffney D, Sun W, Pande V, Thuring JW, Millar H, Poggesi I, Somers I, Boeckx A, Parade M, van Heerde E, Nys T, Yanovich C, Herkert B, Verhulst T, Du Jardin M, Meerpoel L, Moy C, Diels G, Viellevoye M, Schepens W, Poncelet A, Linders JT, Lawson EC, Edwards JP, Chetty D, Laquerre S, Lorenzi MV (2017) A novel PRMT5 inhibitor with potent in vitro and in vivo activity in preclinical lung cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017, Washington, DC Philadelphia (PA): AACR; Cancer Res 77(13 Suppl):Abstract nr DDT02-04 2017

  37. Reddy GR, Thompson WC, Miller SC (2010) Robust light emission from cyclic alkylaminoluciferin substrates for firefly luciferase. J Am Chem Soc 132(39):13586–13587. https://doi.org/10.1021/ja104525m

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhu K, Jiang C, Tao H, Liu J, Zhang H, Luo C (2018) Identification of a novel selective small-molecule inhibitor of protein arginine methyltransferase 5 (PRMT5) by virtual screening, resynthesis and biological evaluations. Bioorg Med Chem Lett 28(9):1476–1483. https://doi.org/10.1016/j.bmcl.2018.03.087

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research work was financially supported by the National Natural Science Foundation of China (No. 81803438), National Science and Technology Major Project (2018ZX09711002-004-013), Shandong Provincial Natural Science Foundation (Nos. JQ201721, ZR2017BH038), the Young Taishan Scholars Program (No. tsqn20161037), and Shandong Talents Team Cultivation Plan of University Preponderant Discipline (No. 10027).

Author information

Author notes

  1. Kongkai Zhu and Jingwei Shao have contributed equally to this work.

Authors and Affiliations

  1. School of Biological Science and Technology, University of Jinan, Jinan, 250022, People’s Republic of China

    Kongkai Zhu, Hongrui Tao, Xue Yan & Hua Zhang

  2. Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai, 201203, People’s Republic of China

    Jingwei Shao & Wenhu Duan

  3. Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People’s Republic of China

    Cheng Luo

Authors
  1. Kongkai Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jingwei Shao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hongrui Tao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xue Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cheng Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hua Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wenhu Duan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Kongkai Zhu, Hua Zhang or Wenhu Duan.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 2261 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhu, K., Shao, J., Tao, H. et al. Rational Design, synthesis and biological evaluation of novel triazole derivatives as potent and selective PRMT5 inhibitors with antitumor activity. J Comput Aided Mol Des 33, 775–785 (2019). https://doi.org/10.1007/s10822-019-00214-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-019-00214-y

Keywords

Search

Navigation