CH5424802, a Selective ALK Inhibitor Capable of Blocking the Resistant Gatekeeper Mutant

• Published in: Cancer cell 2011-05, Vol.19 (5), p.679-690
• Main Authors: Sakamoto, Hiroshi, Tsukaguchi, Toshiyuki, Hiroshima, Sayuri, Kodama, Tatsushi, Kobayashi, Takamitsu, Fukami, Takaaki A., Oikawa, Nobuhiro, Tsukuda, Takuo, Ishii, Nobuya, Aoki, Yuko
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Carbazoles - administration & dosage; Carbazoles - chemistry; Carbazoles - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm - genetics; Humans; Mice; Mice, Nude; Mice, SCID; Models, Molecular; Mutation; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - genetics; Neoplasms - pathology; Piperidines - administration & dosage; Piperidines - chemistry; Piperidines - pharmacology; Protein Conformation; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - chemistry; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Recombinant Fusion Proteins - antagonists & inhibitors; Recombinant Fusion Proteins - metabolism; Time Factors; Transfection; Tumor Burden - drug effects; Xenograft Model Antitumor Assays
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2011.04.004

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. ► Identification of a potent, selective, and orally available ALK inhibitor CH5424802 ► CH5424802 leads to strong tumor regression in cancers with gene alterations of ALK ► Potential efficacy of CH5424802 against the resistant gatekeeper mutant of ALK