PO.CH01.03 · 化学
Discovery of a novel ALK inhibitor ZM-8195 that targets ALK compound mutations with superior TRK selectivity
作者与单位
摘要 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 IC 50 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.
利益披露 Disclosure
Z. Li,
State Key Laboratory of Neurology and Oncology Drug Development, Simcere Zaiming Pharmaceutical Co., Ltd. Employment.
Y. Liu,
State Key Laboratory of Neurology and Oncology Drug Development, Simcere Zaiming Pharmaceutical Co., Ltd. Employment.
M. Li,
State Key Laboratory of Neurology and Oncology Drug Development, Simcere Zaiming Pharmaceutical Co., Ltd. Employment.
J. Dai,
State Key Laboratory of Neurology and Oncology Drug Development, Simcere Zaiming Pharmaceutical Co., Ltd. Employment.
X. Wang,
State Key Laboratory of Neurology and Oncology Drug Development, Simcere Zaiming Pharmaceutical Co., Ltd. Employment.
Y. Cheng,
State Key Laboratory of Neurology and Oncology Drug Development, Simcere Zaiming Pharmaceutical Co., Ltd. Employment.
X. An,
State Key Laboratory of Neurology and Oncology Drug Development, Simcere Zaiming Pharmaceutical Co., Ltd. Employment.
J. Chen,
State Key Laboratory of Neurology and Oncology Drug Development, Simcere Zaiming Pharmaceutical Co., Ltd. Employment.
J. Wang,
State Key Laboratory of Neurology and Oncology Drug Development, Simcere Zaiming Pharmaceutical Co., Ltd. Employment.
Y. Zheng,
State Key Laboratory of Neurology and Oncology Drug Development, Simcere Zaiming Pharmaceutical Co., Ltd. Employment.
W. Li,
State Key Laboratory of Neurology and Oncology Drug Development, Simcere Zaiming Pharmaceutical Co., Ltd. Employment.
L. Xue,
State Key Laboratory of Neurology and Oncology Drug Development, Simcere Zaiming Pharmaceutical Co., Ltd. Employment.
Z. Li,
State Key Laboratory of Neurology and Oncology Drug Development, Simcere Zaiming Pharmaceutical Co., Ltd. Employment.
R. Tang,
State Key Laboratory of Neurology and Oncology Drug Development, Simcere Zaiming Pharmaceutical Co., Ltd. Employment.