Abstract ALK fusions are common oncogenic drivers. Approximately 5% of NSCLC patients are ALK-positive, with 30% to 40% developing brain metastases. ALK inhibitors are primarily used to treat ALK-positive patients. However, sequential therapy with second- and third-generation inhibitors is susceptible to resistance mutations, compromising clinical efficacy. Concurrently, inhibition of TRK-family kinases (TRKA, TRKB, and TRKC) elicits broad central nervous system (CNS) adverse effects, further limiting their utility. Therefore, there is an urgent need to develop a new generation of ALK inhibitors to cover a broader population of drug-resistant mutations with brain penetrance and superior TRK selectivity. Here, we identified ZM-8195, a potent and selective ALK inhibitor. In in vitro evaluation, ZM-8195 showed low nano-molar activities against EML-ALK fusion and G1202R/L1196M mutation in biochemical and cell proliferation assay. ZM-8195 exhibited minimal activity against TRK-family kinases, with selectivity indices for TRKB over ALK wild-type or mutant exceeding 100-fold. ZM-8195 also showed potent anti-proliferation activity in different ALK compound mutant cell lines with IC50 from 0.5-24 nM. ZM-8195 effectively inhibited H3122(EML4-ALK V1) and BaF3(EML4-ALK V1(G1202R/L1196M)) tumor growth with complete tumor regression. In a BaF3 G1202R/L1196M orthotopic brain model, ZM-8195 also demonstrated robust anti-tumor efficacy. ZM-8195 was well tolerated in rodents and non-rodents. Based on its favorable activity, selectivity, pharmacokinetic profiles and safety, ZM-8195 is currently in IND enabling stage. Citation Format: Zhen Li, Yajing Liu, Mengying Li, Jing Dai, Xuefeng Wang, Yuan Cheng, Xue An, Jing Chen, Jianan Wang, Yuandong Zheng, Wenjing Li, Liting Xue, Zhengtao Li, Renghong Tang. Discovery of a novel ALK inhibitor ZM-8195 that targets ALK compound mutations with superior TRK selectivity abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5146.
Li et al. (Fri,) studied this question.