Preclinical evaluation of SIM1803-1A, a small molecule Trk/ROS1 dual inhibitor for wild and mutate NTRK/ROS1 fusion solid malignancies.

作者：Jianfei Wang, Xiaohong Yu, Shunwei Zhu, Qingying Chen, Jikui Sun, Yuanfeng Xia, Yang Zhang, Chi-Chung Chan, Jian Li, Shu‐Hui Chen · 发表于：Journal of Clinical Oncology · 年份：2020 · DOI：10.1200/jco.2020.38.15_suppl.e21663 · 被引用次数：7 · 研究领域：Lung Cancer Treatments and Mutations、Colorectal Cancer Treatments and Studies、Cancer therapeutics and mechanisms

e21663 Background: Fusions and rearrangements of NTRK1/2/3 and ROS1 genes are oncogenic drivers in multiple solid malignancies. Drugs targeting tyrosine kinases TrkA/B/C and ROS1, such as larotrectinib and entrectinib, are proven highly efficacious in diverse adult and pediatric tumor types (ORR > 75%). However, the treatment-related drug resistance, including S.F. mutations, G.K. mutations and DFGx mutations, has been identified in clinical trials. The use of second generation of TKI, such as repotrectinib to against these acquired resistance mutations, has been explored in clinical trials and reported unsatisfied efficacy in patients under acceptable dosages, which might due to its broader inhibition of multiple kinases. Here we report a novel potent Trk/ROS1 dual inhibitor SIM1803-1A, targeting both the wild type and multiple clinical mutations of Trk and ROS1 with clean selectivity profile and expected in vitro and in vivo efficacy for wild and mutant NTRK/ROS1 fusion solid tumors. Methods: Kinase inhibiting potency was determined with Reaction Biology kinase assays. Kinase selectivity was screened on Eurofins Kinase Profiler panel. Cellular anti-proliferative potency was evaluated on relevant fusion cell lines. Antitumor efficacy was evaluated in the related CDX and PDX mice models shown in results. Results: SIM1803-1A displayed high kinase inhibiting potency with IC 50 3.64/1.24 /4.45 nM on TrkA( WT/G595R/G667C) kinase, 0.07/5.03/5.68 nM on TrkC( WT/G623R/L686M), and...