1. Discovery of 4-(4-aminophenyl)-6-phenylisoxazolo[3,4-b]pyridine-3-amine derivatives as novel FLT3 covalent inhibitors for the intervention of acute myeloid leukemia.
- Author
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Wang QX, Wang YB, Sha JK, Zhou H, Liu JC, Wu JZ, Tong ZJ, Cai J, Chen ZJ, Zhang CQ, Zheng XR, Wang JJ, Wang XL, Xue X, Yu YC, Ding N, Leng XJ, Dai WC, Sun SL, Chang L, Li NG, and Shi ZH
- Subjects
- Humans, Cell Line, Tumor, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Pyridines pharmacology, Amines pharmacology, fms-Like Tyrosine Kinase 3 genetics, fms-Like Tyrosine Kinase 3 pharmacology, fms-Like Tyrosine Kinase 3 therapeutic use, Apoptosis, Cell Proliferation, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Leukemia, Myeloid, Acute drug therapy
- Abstract
Small molecule covalent drugs have proved to be desirable therapies especially on drug resistance related to point mutations. Secondary mutations of FLT3 have become the main mechanism of FLT3 inhibitors resistance which further causes the failure of treatment. Herein, a series of 4-(4-aminophenyl)-6-phenylisoxazolo[3,4-b]pyridine-3-amine covalent derivatives were synthesized and optimized to overcome the common secondary resistance mutations of FLT3. Among these derivatives, compound F15 displayed potent inhibition activities against FLT3 (IC
50 = 123 nM) and FLT3-internal tandem duplication (ITD) by 80% and 26.06%, respectively, at the concentration of 1 μM. Besides, F15 exhibited potent activity against FLT3-dependent human acute myeloid leukemia (AML) cell lines MOLM-13 (IC50 = 253 nM) and MV4-11 (IC50 = 91 nM), as well as BaF3 cells with variety of secondary mutations. Furthermore, cellular mechanism assays indicated that F15 inhibited phosphorylation of FLT3 and its downstream signaling factors. Notably, F15 could be considered for further development as potential drug candidate to treat AML., (© 2023 Wiley Periodicals LLC.)- Published
- 2023
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