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

SummaryAnaplastic 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