title: CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant.
abstract: Anaplastic lymphoma kinase (ALK) is a tyrosine kinase that is constitutively activated in certain cancers, following gene alterations such as chromosomal translocation, amplification, or point mutation. Here, we identified CH5424802, a potent, selective, and orally available ALK inhibitor with a unique chemical scaffold, showing preferential antitumor activity against cancers with gene alterations of ALK, such as nonsmall cell lung cancer (NSCLC) cells expressing EML4-ALK fusion and anaplastic large-cell lymphoma (ALCL) cells expressing NPM-ALK fusion in vitro and in vivo. CH5424802 inhibited ALK L1196M, which corresponds to the gatekeeper mutation conferring common resistance to kinase inhibitors, and blocked EML4-ALK L1196M-driven cell growth. Our results support the potential for clinical evaluation of CH5424802 for the treatment of patients with ALK-driven tumors.
authors.affiliation: Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan. sakamotohrs@chugai-pharm.co.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakamoto
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Tsukaguchi
authors.forename: Sayuri
authors.initials: S
authors.lastname: Hiroshima
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Kodama
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Takaaki A
authors.initials: TA
authors.lastname: Fukami
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Oikawa
authors.forename: Takuo
authors.initials: T
authors.lastname: Tsukuda
authors.forename: Nobuya
authors.initials: N
authors.lastname: Ishii
authors.forename: Yuko
authors.initials: Y
authors.lastname: Aoki
mesh_terms: D000284:Administration, Oral; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002227:Carbazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D008958:Models, Molecular; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002227:Carbazoles; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011993:Recombinant Fusion Proteins; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C582670:alectinib