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Background: Up to date, over 80 small molecule kinase inhibitors have been approved for the treatment of cancers worldwide. This class of targeted therapy benefits millions of patients by improving their disease management and quality of life. However, acquired drug resistance can develop quickly after treatment in most of the patients. Herein, we disclose TSN084, a unique small molecule multi-kinase inhibitor, which can overcome many common acquired drug-resistant mutations of cMet, Trks, and Flt3, etc. It also inhibits other oncotargets including Axl, DDRs, and CDK8/19. Method: The primary screen of TSN084 against 468 kinases at a single concentration was carried out by Eurofins DiscoverX Corporation. Its inhibitory activity on interested kinases and relevant cellular proliferation were determined separately. A series of cell-derived xenograft (CDX) models were used to evaluate its in vivo antitumor effect. Both in vitro and in vivo PK study was performed in mouse, rat, dog, and monkey. An in vitro safety panel and in vivo GLP animal studies were carried out to assess its preliminary toxicity profile in preparation for human clinical trials. Results: Kinase activity profiling assay revealed that TSN084 is a multi-kinase inhibitor. Among the 468 kinases tested, 33 showed >50% inhibition at 0.1 uM, including many oncotargets and their mutants such as Met, Met-Y1235D, Met-M1250T, Flt3, Flt3-N841I, Flt3-ITD, Flt3-K663Q, Flt3-D835Y, Flt3-D835V, Axl, TrkA, DDR1, and CDK8/19. It demonstrated potent anti-proliferation activity against many tumor cell lines, e.g. KM12, MKN45, MV-4-11, and HS746T. It also effectively inhibited tumor growth in several CDX drug-resistant models like NTRK-G667C and NTRK3-G696C and showed outstanding survival advantage. TSN084 is an orally bioavailable small molecule agent in mouse, rat, dog, and monkey. It is clean in a safety panel assessment of 44 concerning targets and considered safe enough to advance into clinical study. Conclusion: TSN084 targets several oncogenic kinases and their drug-resistant mutants. It demonstrated potent antitumor effects in both in vitro and in vivo studies. It showed excellent PK properties and acceptable preclinical safety profile. A phase I clinical trial of TSN084 in patients with advanced or metastatic malignancies is currently ongoing (NCT05300438). As of Oct 30, 2022, 6 patients have been enrolled into the trial, and no DLTs or treatment-related AEs were observed. It is a promising agent for the potential treatment of resistant cancers in the clinic. Citation Format: Boyu Zhong, Tony Zhang, Chunlan Dong, Shengtang Mark Ma, Ziyang Jia, Guangming Chen, Renjuan Zheng, Jing Cindy Li, Han Fu. TSN084, a multi-kinase inhibitor, overcomes acquired drug-resistant mutations of cMet, Trks, and Flt3, and displays broad activities against kinase oncotargets Axl, DDRs, and CDK8/19. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4027.