Discovery of a Potent FLT3 Inhibitor (LT-850-166) with the Capacity of Overcoming a Variety of FLT3 Mutations

• Published in: Journal of medicinal chemistry Vol. 64; no. 19; pp. 14664 - 14701
• Main Authors: Wang, Zhijie, Cai, Jiongheng, Ren, Jiwei, Chen, Yun, Wu, Yingli, Cheng, Jie, Jia, Kun, Huang, Fei, Cheng, Zitian, Sheng, Tiancheng, Song, Shiyu, Heng, Hao, Zhu, Yifan, Tang, Weifang, Li, Hongmei, Lu, Tao, Chen, Yadong, Lu, Shuai
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.10.2021; Amer Chemical Soc
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; Drug Discovery; Drug Resistance, Neoplasm - drug effects; fms-Like Tyrosine Kinase 3 - antagonists & inhibitors; fms-Like Tyrosine Kinase 3 - genetics; Humans; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - pathology; Life Sciences & Biomedicine; Molecular Dynamics Simulation; Mutation; Pharmacology & Pharmacy; Science & Technology; Structure-Activity Relationship; Xenograft Model Antitumor Assays; AML; MIDOSTAURIN; RESISTANCE; ACUTE MYELOID-LEUKEMIA; KINASE INHIBITOR; QUIZARTINIB; CHEMOTHERAPY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c01196

Secondary mutations of FLT3 have become the main mechanism of FLT3 inhibitor resistance that presents a significant clinical challenge. Herein, a series of pyrazole-3-amine derivatives were synthesized and optimized to overcome the common secondary resistance mutations of FLT3. The structure–activity relationship and molecular dynamics simulation studies illustrated that the ribose region of FLT3 could be occupied to help address the obstacle of secondary mutations. Among those derivatives, compound 67 exhibited potent and selective inhibitory activities against FLT3-ITD-positive acute myeloid leukemia (AML) cells and possessed equivalent potency against transformed BaF3 cells with a variety of secondary mutations. Besides, cellular mechanism assays demonstrated that 67 strongly inhibited phosphorylation of FLT3 and its downstream signaling factors, as well as induced cell cycle arrest and apoptosis in MV4-11 cells. In the MV4-11 xenograft models, 67 exhibited potent antitumor potency without obvious toxicity. Taken together, these results demonstrated that 67 might be a drug candidate for the treatment of FLT3-ITD-positive AML.