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7491511 
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 
2016 
Yes 
Journal of Medicinal Chemistry
ISSN: 0022-2623
EISSN: 1520-4804 
American Chemical Society 
59 
14 
6671-6689 
English 
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