title: 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.
abstract: 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.
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John J. Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Gérald
authors.initials: G
authors.lastname: Lelais
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John J. Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Epple
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John J. Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Marsilje
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John J. Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Yun O
authors.initials: YO
authors.lastname: Long
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John J. Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Matthew
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authors.lastname: McNeill
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John J. Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Bei
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authors.lastname: Chen
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John J. Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Wenshuo
authors.initials: W
authors.lastname: Lu
authors.affiliation: Aurigene Discovery Technologies , Bollaram Road, Miyapur, Hyderabad 500 049, India.
authors.forename: Jaganmohan
authors.initials: J
authors.lastname: Anumolu
authors.affiliation: Aurigene Discovery Technologies , 39-40, Electronic City Phase 2, Bangalore 560 100, India.
authors.forename: Sangamesh
authors.initials: S
authors.lastname: Badiger
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John J. Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Badry
authors.initials: B
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authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John J. Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Michael
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authors.lastname: DiDonato
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John J. Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Rina
authors.initials: R
authors.lastname: Fong
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John J. Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Jose
authors.initials: J
authors.lastname: Juarez
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John J. Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Jie
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authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John J. Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Mari
authors.initials: M
authors.lastname: Manuia
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John J. Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Mason
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John J. Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Perry
authors.initials: P
authors.lastname: Gordon
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John J. Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Todd
authors.initials: T
authors.lastname: Groessl
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John J. Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Johnson
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John J. Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Yong
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John J. Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Shailaja
authors.initials: S
authors.lastname: Kasibhatla
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John J. Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Chun
authors.initials: C
authors.lastname: Li
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John J. Hopkins Drive, San Diego, California 92121, United States.
authors.forename: John
authors.initials: J
authors.lastname: Isbell
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John J. Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Glen
authors.initials: G
authors.lastname: Spraggon
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John J. Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Bender
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John J. Hopkins Drive, San Diego, California 92121, United States.
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authors.initials: PY
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mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D009538:Nicotine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D009538:Nicotine; D066246:ErbB Receptors; C000619734:nazartinib