Oxopyrido[2,3-d]pyrimidines as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors.

In nonsmall cell lung cancer (NSCLC), the threonine(790)-methionine(790) (T790M) point mutation of EGFR kinase is one of the leading causes of acquired resistance to the first generation tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. Herein, we describe the optimization of a series of 7-oxopyrido[2,3-d]pyrimidinyl-derived irreversible inhibitors of EGFR kinase. This led to the discovery of compound 24 which potently inhibits gefitinib-resistant EGFR(L858R,T790M) with 100-fold selectivity over wild-type EGFR. Compound 24 displays strong antiproliferative activity against the H1975 nonsmall cell lung cancer cell line, the first line mutant HCC827 cell line, and promising antitumor activity in an EGFR(L858R,T790M) driven H1975 xenograft model sparing the side effects associated with the inhibition of wild-type EGFR.

[1]  Wei Huang,et al.  A chemical tuned strategy to develop novel irreversible EGFR-TK inhibitors with improved safety and pharmacokinetic profiles. , 2014, Journal of medicinal chemistry.

[2]  Siew K. Yeap,et al.  Discovery of Selective and Noncovalent Diaminopyrimidine-Based Inhibitors of Epidermal Growth Factor Receptor Containing the T790M Resistance Mutation , 2014, Journal of medicinal chemistry.

[3]  Peter Ballard,et al.  Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. , 2014, Journal of medicinal chemistry.

[4]  W. Pao,et al.  AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. , 2014, Cancer discovery.

[5]  A. Kulkarni,et al.  A proposed screening paradigm for discovery of covalent inhibitor drugs. , 2014, Drug metabolism letters.

[6]  Ryan P. Wurz,et al.  Pyridin-2-one synthesis using ester enolates and aryl aminoaldehydes and ketones. , 2014, The Journal of organic chemistry.

[7]  G. Giaccone,et al.  A phase 2 trial of dacomitinib (PF‐00299804), an oral, irreversible pan‐HER (human epidermal growth factor receptor) inhibitor, in patients with advanced non–small cell lung cancer after failure of prior chemotherapy and erlotinib , 2014, Cancer.

[8]  P. Kuzmič,et al.  Covalent EGFR inhibitor analysis reveals importance of reversible interactions to potency and mechanisms of drug resistance , 2013, Proceedings of the National Academy of Sciences.

[9]  P. Jänne,et al.  The quest to overcome resistance to EGFR-targeted therapies in cancer , 2013, Nature Medicine.

[10]  Ke Ding,et al.  Design, synthesis, and biological evaluation of 2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidinyl derivatives as new irreversible epidermal growth factor receptor inhibitors with improved pharmacokinetic properties. , 2013, Journal of medicinal chemistry.

[11]  Ke Ding,et al.  Discovery of pteridin-7(8H)-one-based irreversible inhibitors targeting the epidermal growth factor receptor (EGFR) kinase T790M/L858R mutant. , 2013, Journal of medicinal chemistry.

[12]  Juswinder Singh,et al.  Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. , 2013, Cancer discovery.

[13]  Matthew Grist,et al.  Structure- and reactivity-based development of covalent inhibitors of the activating and gatekeeper mutant forms of the epidermal growth factor receptor (EGFR). , 2013, Journal of medicinal chemistry.

[14]  G. Keating,et al.  Afatinib: First Global Approval , 2013, Drugs.

[15]  Honglin Li,et al.  Pyrimido[4,5-d]pyrimidin-4(1H)-one derivatives as selective inhibitors of EGFR threonine790 to methionine790 (T790M) mutants. , 2013, Angewandte Chemie.

[16]  K. Leach,et al.  High throughput glutathione and Nrf2 assays to assess chemical and biological reactivity of cysteine-reactive compounds , 2013 .

[17]  William Pao,et al.  Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  Yoshikazu Ohta,et al.  Structure-Based Approach for the Discovery of Pyrrolo[3,2-d]pyrimidine-Based EGFR T790M/L858R Mutant Inhibitors. , 2013, ACS medicinal chemistry letters.

[19]  J. Settleman,et al.  Noncovalent wild-type-sparing inhibitors of EGFR T790M. , 2013, Cancer discovery.

[20]  S. Ou.  Second-generation irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs): a better mousetrap? A review of the clinical evidence. , 2012, Critical reviews in oncology/hematology.

[21]  Juswinder Singh,et al.  Superiority of a novel EGFR targeted covalent inhibitor over its reversible counterpart in overcoming drug resistance , 2012 .

[22]  A. Kaptein,et al.  Irreversible protein kinase inhibitors: balancing the benefits and risks. , 2012, Journal of medicinal chemistry.

[23]  Ke Ding,et al.  Design, synthesis, and biological evaluation of novel conformationally constrained inhibitors targeting epidermal growth factor receptor threonine⁷⁹⁰ → methionine⁷⁹⁰ mutant. , 2012, Journal of medicinal chemistry.

[24]  Susan Quinn,et al.  Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: results of a phase II trial in patients with advanced non-small-cell lung cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  S. Chmait,et al.  Discovery and evaluation of 7-alkyl-1,5-bis-aryl-pyrazolopyridinones as highly potent, selective, and orally efficacious inhibitors of p38alpha mitogen-activated protein kinase. , 2010, Journal of medicinal chemistry.

[26]  John R. Engen,et al.  Novel mutant-selective EGFR kinase inhibitors against EGFR T790M , 2009, Nature.

[27]  S. Chmait,et al.  Part 1: Structure-Activity Relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38alpha mitogen-activated protein kinase. , 2009, Bioorganic & medicinal chemistry letters.

[28]  M. Potashman,et al.  Covalent modifiers: an orthogonal approach to drug design. , 2009, Journal of medicinal chemistry.

[29]  M. Meyerson,et al.  The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP , 2008, Proceedings of the National Academy of Sciences.

[30]  P. Workman,et al.  Application of meso scale technology for the measurement of phosphoproteins in human tumor xenografts. , 2007, Assay and drug development technologies.

[31]  Daniel A. Haber,et al.  Epidermal growth factor receptor mutations in lung cancer , 2007, Nature Reviews Cancer.

[32]  Ramaswamy Nilakantan,et al.  Antitumor Activity of HKI-272, an Orally Active, Irreversible Inhibitor of the HER-2 Tyrosine Kinase , 2004, Cancer Research.

[33]  O. H. Chan,et al.  Tyrosine kinase inhibitors. 17. Irreversible inhibitors of the epidermal growth factor receptor: 4-(phenylamino)quinazoline- and 4-(phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides bearing additional solubilizing functions. , 2000, Journal of medicinal chemistry.