Journal Article
Discovery of (R,E)-N-(7-chloro-1-(1-[4-(dimethylamino)but-2-enoyl]azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide (EGF816), a novel, potent, and WT sparing covalent inhibitor of oncogenic (L858R, ex19del) and resistant (T790M) EGFR mutants for the treatment of EGFR mutant non-small-cell lung cancers
Lelais, G; Epple, R; Marsilje, TH; Long, YO; Mcneill, M; Chen, B; Lu, W; Anumolu, J; Badiger, S; Bursulaya, B; Didonato, M; Fong, R; Juarez, J; Li, J; Manuia, M; Mason, DE; Gordon, P; Groessl, T; Johnson, K; Jia, Y; Kasibhatla, S; Li, C; Isbell, J; Spraggon, G; Bender, S; Michellys, PY
Journal of Medicinal Chemistry
ISSN: 0022-2623
EISSN: 1520-4804
American Chemical Society
Over the past decade, first and second generation EGFR inhibitors have significantly improved outcomes for lung cancer patients with activating mutations in EGFR. However, both resistance through a secondary T790M mutation at the gatekeeper residue and dose-limiting toxicities from wild-type (WT) EGFR inhibition ultimately limit the full potential of these therapies to control mutant EGFR-driven tumors and new therapies are urgently needed. Herein, we describe our approach toward the discovery of 47 (EGF816, nazartinib), a novel, covalent mutant-selective EGFR inhibitor with equipotent activity on both oncogenic and T790M-resistant EGFR mutations. Through molecular docking studies we converted a mutant-selective high-throughput screening hit (7) into a number of targeted covalent EGFR inhibitors with equipotent activity across mutants EGFR and good WT-EGFR selectivity. We used an abbreviated in vivo efficacy study for prioritizing compounds with good tolerability and efficacy that ultimately led to the selection of 47 as the clinical candidate. © 2016 American Chemical Society.
afatinib; epidermal growth factor receptor; epidermal growth factor receptor kinase inhibitor; nazartinib; tert butyl 3 [(2 chloro 6 nitrophenyl)amino]azepane 1 carboxylate; tert butyl 3 [(2 methyl 6 nitrophenyl)amino]azepane 1 carboxylate; tert butyl 3 [(4 methyl 2 nitrophenyl)amino]azepane 1 carboxylate; tert butyl 3 [(4 methyl 2 nitrophenyl)amino]azetidine 1 carboxylate; tert butyl 3 [(4 methyl 2 nitrophenyl)amino]piperidine 1 carboxylate; tert butyl 3 [(4 methyl 2 nitrophenyl)amino]pyrrolidine 1 carboxylate; tert butyl 4 [(4 methyl 2 nitrophenyl)amino]azepane 1 carboxylate; tert butyl 4 [(4 methyl 2 nitrophenyl)amino]piperidine 1 carboxylate; tert butyl cis [2 [(4 methyl 2 nitrophenyl)amino]cyclohexyl]carbamate; tert butyl cis [3 [(4 methyl 2 nitrophenyl)amino]cyclohexyl]carbamate; tert butyl cis [4 [(4 methyl 2 nitrophenyl)amino]cyclohexyl]carbamate; tert butyl methyl[3 [(4 methyl 2 nitrophenyl)amino]phenyl]carbamate; tert butyl trans [2 [(4 methyl 2 nitrophenyl)amino]cyclohexyl]carbamate; tert butyl trans [3 [(4 methyl 2 nitrophenyl)amino]cyclohexyl]carbamate; tert butyl trans [4 [(4 methyl 2 nitrophenyl)amino]cyclohexyl]carbamate; tert butyl [2 [(4 methyl 2 nitrophenyl)amino]ethyl]carbamate; tert butyl [2 [(4 methyl 2 nitrophenyl)amino]phenyl]carbamate; tert butyl [3 [(4 methyl 2 nitrophenyl)amino]cyclopentyl]carbamate; tert butyl [3 [(4 methyl 2 nitrophenyl)amino]phenyl]carbamate; tert butyl [3 [(4 methyl 2 nitrophenyl)amino]propyl]carbamate; trans 4 [(2 methyl 2 nitrophenyl)amino]cyclohexan 1 ol; trans 4 [(2 nitrophenyl)amino]cyclohexan 1 ol; trans 4 [(3 methyl 2 nitrophenyl)amino]cyclohexan 1 ol; trans 4 [(4 methyl 2 nitrophenyl)amino]cyclohexan 1 ol; trans 4 [(5 methyl 2 nitrophenyl)amino]cyclohexan 1 ol; unclassified drug; unindexed drug; (R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo(d)imidazol-2-yl)-2-methylisonicotinamide; antineoplastic agent; benzimidazole derivative; epidermal growth factor receptor; nicotine; protein kinase inhibitor; Article; cancer patient; controlled study; drug efficacy; drug screening; drug tolerability; female; gene mutation; high throughput screening; human; human cell; in vivo study; male; molecular docking; mouse; non small cell lung cancer; nonhuman; rat; analogs and derivatives; animal; antagonists and inhibitors; Bagg albino mouse; Carcinoma, Non-Small-Cell Lung; cell proliferation; chemistry; conformation; dose response; drug development; drug effects; enzymology; genetics; Lung Neoplasms; metabolism; molecular model; mutation; Neoplasms, Experimental; nude mouse; pathology; structure activity relation; synthesis; Wistar rat; X ray crystallography; Animals; Antineoplastic Agents; Benzimidazoles; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Humans; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Models, Molecular; Molecular Conformation; Mutation; Neoplasms, Experimental; Nicotine; Protein Kinase Inhibitors; Rats; Rats, Wistar; Receptor, Epidermal Growth Factor; Structure-Activity Relationship