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SAF-189s, a potent new-generation ROS1 inhibitor, is active against crizotinib-resistant ROS1 mutant-driven tumors

文献类型：期刊论文

作者Xia, Zong-jun1,2,3; Ji, Yin-chun2,3; Sun, De-qiao1,2,3; Peng, Xia2,3; Gao, Ying-lei2,3; Fang, Yan-fen2,3; Zhao, Xing-dong4; Wang, Wei-bo4; Ding, Jian2,3; Geng, Mei-yu1,2,3
刊名ACTA PHARMACOLOGICA SINICA
出版日期2020-09-11
页码7
关键词ROS1 kinase ROS1 inhibitor SAF-189s lorlatinib crizotinib resistance G2032R mutant NSCLC
ISSN号1671-4083
DOI10.1038/s41401-020-00513-3
通讯作者Ai, Jing(jai@simm.ac.cn)
英文摘要The ROS1 fusion kinase is an attractive antitumor target. Though with significant clinical efficacy, the well-known first-generation ROS1 inhibitor (ROS1i) crizotinib inevitably developed acquired resistance due to secondary point mutations in the ROS1 kinase. Novel ROS1is effective against mutations conferring secondary crizotinib resistance, especially G2032R, are urgently needed. In the present study, we evaluated the antitumor efficacy of SAF-189s, the new-generation ROS1/ALK inhibitor, against ROS1 fusion wild-type and crizotinib-resistant mutants. We showed that SAF-189s potently inhibited ROS1 kinase and its known acquired clinically resistant mutants, including the highly resistant G2032R mutant. SAF-189s displayed subnanomolar to nanomolar IC(50)values against ROS1 wild-type and mutant kinase activity and a selectivity vs. other 288 protein kinases tested. SAF-189s blocked cellular ROS1 signaling, and in turn potently inhibited the cell proliferation in HCC78 cells and BaF3 cells expressing ROS1 fusion wild-type and resistance mutants. In nude mice bearing BaF3/CD74-ROS1 or BaF3/CD74-ROS1(G2032R)xenografts, oral administration of SAF-189s dose dependently suppressed the growth of both ROS1 wild-type- and G2032R mutant-driven tumors. In a patient-derived xenograft model of SDC4-ROS1 fusion NSCLC, oral administration of SAF-189s (20 mg/kg every day) induced tumor regression and exhibited notable prolonged and durable efficacy. In addition, SAF-189s was more potent than crizotinib and comparable to lorlatinib, the most advanced ROS1i known against the ROS1(G2032R). Collectively, these results suggest the promising potential of SAF-189s for the treatment of patients with the ROS1 fusion G2032R mutation who relapse on crizotinib. It is now recruiting both crizotinib-relapsed and naive ROS1-positive NSCLC patients in a multicenter phase II trial (ClinicalTrials.gov Identifier: NCT04237805).
WOS关键词TARGETING ROS1 ; LUNG-CANCER ; FUSIONS ; MUTATION
资助项目Personalized Medicines-Molecular Signature-based Drug Discovery and Development Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020000] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020103] ; Natural Science Foundation of China for Innovation Research Group[81821005] ; Natural Science Foundation of China[81773762] ; Natural Science Foundation of China[81473243] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program of China[2018ZX09711002-011-013] ; Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning[2020CXJQ02]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000568465900001
出版者NATURE PUBLISHING GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/291131]  
专题新药研究国家重点实验室
通讯作者Ai, Jing
作者单位1.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Fochon Pharmaceut Ltd, Chongqing 401123, Peoples R China
推荐引用方式
GB/T 7714		 Xia, Zong-jun,Ji, Yin-chun,Sun, De-qiao,et al. SAF-189s, a potent new-generation ROS1 inhibitor, is active against crizotinib-resistant ROS1 mutant-driven tumors[J]. ACTA PHARMACOLOGICA SINICA,2020:7.
APA Xia, Zong-jun.,Ji, Yin-chun.,Sun, De-qiao.,Peng, Xia.,Gao, Ying-lei.,...&Ai, Jing.(2020).SAF-189s, a potent new-generation ROS1 inhibitor, is active against crizotinib-resistant ROS1 mutant-driven tumors.ACTA PHARMACOLOGICA SINICA,7.
MLA Xia, Zong-jun,et al."SAF-189s, a potent new-generation ROS1 inhibitor, is active against crizotinib-resistant ROS1 mutant-driven tumors".ACTA PHARMACOLOGICA SINICA (2020):7.

入库方式： OAI收割

来源：上海药物研究所

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