PO.CH01.03 · 化学
发现一种新型ALK抑制剂ZM-8195,靶向ALK复合突变并具有优越的TRK选择性
Discovery of a novel ALK inhibitor ZM-8195 that targets ALK compound mutations with superior TRK selectivity
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
ALK融合是常见的致癌驱动因素。约5%的NSCLC患者为ALK阳性,其中30%至40%会发生脑转移。ALK抑制剂主要用于治疗ALK阳性患者。然而,采用第二代和第三代抑制剂的序贯治疗易受耐药突变的影响,从而损害临床疗效。同时,对TRK家族激酶(TRKA、TRKB和TRKC)的抑制会引发广泛的中枢神经系统(CNS)不良反应,进一步限制了其应用。因此,迫切需要开发新一代ALK抑制剂,以覆盖更广泛的耐药突变人群,并具有脑穿透性和优越的TRK选择性。在此,我们鉴定出ZM-8195,一种强效且选择性的ALK抑制剂。在体外评估中,ZM-8195在生化和细胞增殖实验中对EML-ALK融合以及G1202R/L1196M突变显示出低纳摩尔级的活性。ZM-8195对TRK家族激酶表现出极低的活性,TRKB相对于ALK野生型或突变型的选择性指数超过100倍。ZM-8195在不同的ALK复合突变细胞系中也显示出强效的抗增殖活性,IC50为0.5-24 nM。ZM-8195有效抑制了H3122(EML4-ALK V1)和BaF3(EML4-ALK V1(G1202R/L1196M))的肿瘤生长,实现完全的肿瘤消退。在BaF3 G1202R/L1196M原位脑模型中,ZM-8195也展现出强劲的抗肿瘤疗效。ZM-8195在啮齿类和非啮齿类动物中均具有良好的耐受性。基于其良好的活性、选择性、药代动力学特征和安全性,ZM-8195目前正处于IND申报准备阶段。
查看英文原文 English 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.