Synthesis and Biological Evaluation of Oxopyrido[2,3-d] Pyrimidine-7- ones Derivatives as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors

Author(s): Ao Niu, Yang Wang, Yushe Yang*, Jianhai Wei, Jian Ding, Yi Chen, Linjiang Tong, Hua Xie

Journal Name: Letters in Drug Design & Discovery

Volume 16 , Issue 8 , 2019

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Background: None small cell cancer (NSCLC) is one of the most common cancer around the globe. First generation EGFR-TKI such as gefitinib and erlotinib are now documentated a prolonged PFS in NSCLC patients with EGFR activating mutation. However, upon continuous treatment, patients become resistant due toCEE T790M mutation in most cases.Second generation covalent EGFR inhibitors like afatinib have a moderate inhibition to EGFRT790M in preclinical models,but it is lacking efficacy in the clinical use for patients with T790M mutation due to the dose-limiting EGFRWT-driven toxicities.Third generation EGFR inhibitors have the potential to overcome EGFRT790M resistance mutations while reducing EGFRWT-driven toxicities and are now under active research.

Methods: We took compound 6 as our lead compound. We focused on structural modifications around the hydrophile side chain, the linker, and the Micheal addition receptor moiety of AMG. A novel series of Oxopyrido[2,3-d]pyrimidine-7-ones derivatives have been designed and synthesized. Their kinase inhibition activity against EGFRWT and EGFRL858R/T790M were tested by ELISA assays. SRB test was used for cellular anti-proliferation evaluation.

Results: A total of 21 novel Oxopyrido[2,3-d]pyrimidine-7-ones derivatives have been designed and synthesized. The compounds were characterized with 1H-NMR and HRMS. Their structureactivity relationships have been preliminaryly investigated. As a result, compound 7k showed comparable activity in kinase inhibition assay and cell growth inhibition assay with our lead compound 6. Higher activity and selectivity over EGFRWT were observed in the in vitro antitumour assay comparing compound 7k to AZD-9291. Compound 7a exhibited higher selectivity over EGFRWT in kinase inhibition assay, but poor cell inhibition to NCI-1975 cell line. The in vivo pharmacokinetic studies in rats showed that compound 9a exhibited improved pharmacokinetic profiles comparing to 6. Compound 9a was also efficacious in an NCI-H1975 murine xenograft model 30 mg/kg QD.

Conclusion: Compound 9a has a potent kinase inhibition to EGFRT790M and has a high selectivity over EGFRWT. It’s also efficacious in an in vivo pharmacodynamic evaluation assay. Significant advantages were observed in pharmacokinetic evaluation comparing 9a to 6, which provide us a reference to further drug design and research.

Keywords: Non-small cell lung cancer, irreversible inhibitors, EGFRT790M mutant, anti-tumor, xenograft model, cell proliferation.

Ferlay, J.; Soerjomataram, I.; Dikshit, R.; Eser, S.; Mathers, C.; Rebelo, M.; Parkin, D.M.; Forman, D.; Bray, F. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer, 2015, 136(5), E359-E386.
Normanno, N. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene, 2006, 366(1), 2-16.
Barker, A.J.; Gibson, K.H.; Grundy, W.; Godfrey, A.A.; Barlow, J.J.; Healy, M.P.; Woodburn, J.R.; Ashton, S.E.; Curry, B.J.; Scarlett, L.; Henthorn, L.; Richards, L. Studies leading to the identification of ZD1839 (iressa™): An orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor targeted to the treatment of cancer. Bioorg. Med. Chem. Lett., 2001, 11(14), 1911-1914.
Moyer, J.D.; Barbacci, E.G.; Iwata, K.K.; Arnold, L.; Boman, B.; Cunningham, A.; DiOrio, C.; Doty, J.; Morin, M.J.; Moyer, M.P.; Neveu, M.; Pollack, V.A.; Pustilnik, L.R.; Reynolds, M.M.; Sloan, D.; Theleman, A.; Miller, P. Induction of apoptosis and cell cycle arrest by CP-358,774, an Inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res., 1997, 57(21), 4838.
Zhao, Q.; Shentu, J.; Xu, N.; Zhou, J.; Yang, G.; Yao, Y.; Tan, F.; Liu, D.; Wang, Y.; Zhou, J. Phase I study of icotinib hydrochloride (BPI-2009H), an oral EGFR tyrosine kinase inhibitor, in patients with advanced NSCLC and other solid tumors. Lung Cancer, 2011, 73(2), 195-202.
Chan, S.K.; Gullick, W.J.; Hill, M.E. Mutations of the epidermal growth factor receptor in non-small cell lung cancer - Search and destroy. Eur. J. Cancer, 2006, 42(1), 17-23.
Pao, W.; Katerina, A.P.; Gregory, J.R.; Romel, S.; Maureen, F.Z.; Mark, G.K. Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase Domain. PLoS Med., 2005, 2(3), e73.
Yun, C.H.; Mengwasser, K.E.; Toms, A.V.; Woo, M.S.; Greulich, H.; Wong, K.K.; Meyerson, M.; Eck, M.J. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc. Natl. Acad. Sci. USA, 2008, 105(6), 2070-2075.
Ou, S.I. Second-generation irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs): A better mousetrap? A review of the clinical evidence. Crit. Rev. Oncol. Hematol., 2012, 83(3), 407-421.
aEngelman, J.A.; Zejnullahu, K.; Gale, C.M.; Lifshits, E.; Gonzales, A.J.; Shimamura, T.; Zhao, F.; Vincent, P.W.; Naumov, G.N.; Bradner, J.E.; Althaus, I.W.; Gandhi, L.; Shapiro, G.I.; Nelson, J.M.; Heymach, J.V.; Meyerson, M.; Wong, K.K.; Jänne, P.A. PF00299804, an Irreversible Pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res., 2007, 67(24), 11924.
bLi, D.; Ambrogio, L.; Shimamura, T.; Kubo, S.; Takahashi, M.; Chirieac, L.R.; Padera, R.F.; Shapiro, G.I.; Baum, A.; Himmelsbach, F.; Rettig, W.J.; Meyerson, M.; Solca, F.; Greulich, H.; Wong, K. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene, 2008, 27, 4702.
Cheng, H.; Nair, S.K.; Murray, B.W. Recent progress on third generation covalent EGFR inhibitors. Bioorg. Med. Chem. Lett., 2016, 26(8), 1861-1868.
Zhou, W.; Ercan, D.; Chen, L.; Yun, C.H.; Li, D.; Capelletti, M.; Cortot, A.B.; Chirieac, L.; Iacob, R.E.; Padera, R.; Engen, J.R.; Wong, K.K.; Eck, M.J.; Gray, N.S.; Jänne, P.A. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature, 2009, 462(7276), 1070-1074.
Walter, A.O.; Sjin, R.T.; Haringsma, H.J.; Ohashi, K.; Sun, J.; Lee, K.; Dubrovskiy, A.; Labenski, M.; Zhu, Z.; Wang, Z.; Sheets, M.; St-Martin, T.; Karp, R.; van Kalken, D.; Chaturvedi, P.; Niu, D.; Nacht, M.; Petter, R.C.; Westlin, W.; Lin, K.; Jaw-Tsai, S.; Raponi, M.; Van Dyke, T.; Etter, J.; Weaver, Z.; Pao, W.; Singh, J.; Simmons, A.D.; Harding, T.C.; Allen, A. Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. Cancer Discov., 2013, 3(12), 1404.
Finlay, M.R.V.; Anderton, M.; Ashton, S.; Ballard, P.; Bethel, P.A.; Box, M.R. Bradbury, R.H.; Brown, S.J.; Butterworth, S.; Campbell, A.; Chorley, C.; Colclough, N.; Cross, D.A.; Currie, G.S.; Gris,t M.; Hassall, L.; Hill, G.B.; James, D.; James, M.; Kemmitt, P.; Klinowska, T.; Lamont, G.; Lamont, S.G.; Martin, N.; McFarland, H.L.; Mellor, M.J.; Orme, J.P.; Perkins, D.; Perkins, P.; Richmond, G.; Smith, P.; Ward, R.A.; Waring, M.J.; Whittaker, D.; Wells, S.; Wrigley, G.L. Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M re-sistance mutations that spares the wild type form of the receptor. J. Med. Chem., 2014, 57(20), 8249-8267.
Janne, P.A.; Yang, J.C.; Kim, D.W.; Planchard, D.; Ohe, Y.; Ra-malingam, S.S.; Ahn, M.J.; Kim, S.W.; Su, W.C.; Horn, L.; Haggstrom, D.; Felip, E.; Kim, J.H.; Frewer, P.; Cantarini, M.; Brown, K.H.; Dickinson, P.A.; Ghiorghiu, S.; Ranson, M. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N. Engl. J. Med., 2015, 372(18), 1689-1699.
Wurz, R.P.; Pettus, H.L.; Ashton, K.; Brown, J.; Chen, J.J.; Herberich, B.; Hong, F-T.; Hu-Harrington, E.; Nguyen, T.; St. Jean, J.D., Jr Tadesse, Seifu.; Bauer, D.; Kubryk, M.; Zhan, J.; Cooke, K.; Mitchel, P.; Andrews, L. K.; Hsieh, F.; Hick-man, D.; Kalyanaraman, N.; Wu, T.; Reid, L.D.; Lobenhofer, E. K.; Andrews, D. A.; Everds, Nancy.; Guzman, R.; Parsons, A.T.; Hedley, J.S.; Tedrow, J.; Thiel, R.O.; Potter, M.; Ra-dinsky, R.; Beltran, J. P.; Tasker, A.S. Oxopyrido[2,3-d]pyrimidines as covalent L858R/T790M Mutant selective epidermal growth factor receptor (EGFR) inhibitors. ACS Med. Chem. Lett., 2015, 6(9), 987-992.
Xia, G.; Chen, W.; Zhang, J. Shaao, J.; Zhang, Y.; Huang, W.; Zhang, L.; Qi, W.; Sun, X.; Li, B.; Xiang, Z.; Ma, C.; Xu, J.; Deng, H.; Li, Y.; Li, P.; Mia, H.; Han, J.; Li, Y.; Shen, J.; Yu, Y. A chemical tuned strategy to develop novel irreversible EGFR-TK inhibitors with improved safety and pharmacokinetic profiles. J. Med. Chem., 2014, 57(23), 9889-9900.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Published on: 22 May, 2018
Page: [826 - 834]
Pages: 9
DOI: 10.2174/1570180815666180523090558
Price: $65

Article Metrics

PDF: 43