Discovery of indirubin-3'-aminooxy-acetamide derivatives as potent and selective FLT3/D835Y mutant kinase inhibitors for acute myeloid leukemia.
Autor: | Lee JH; School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, South Korea., Shin JE; Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, South Korea., Kim W; School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, South Korea., Jeong P; R&D Center, PeLeMed, Co. Ltd., Seoul, 06100, South Korea; Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, 61005, South Korea., Kim MJ; R&D Center, PeLeMed, Co. Ltd., Seoul, 06100, South Korea., Oh SJ; R&D Center, PeLeMed, Co. Ltd., Seoul, 06100, South Korea., Lee HJ; College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Gyeongsangnam-do, 52828, South Korea., Park HW; Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, South Korea. Electronic address: hwp003@yonsei.ac.kr., Han SY; College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Gyeongsangnam-do, 52828, South Korea. Electronic address: syhan@gnu.ac.kr., Kim YC; School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, South Korea; R&D Center, PeLeMed, Co. Ltd., Seoul, 06100, South Korea. Electronic address: yongchul@gist.ac.kr. |
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Jazyk: | angličtina |
Zdroj: | European journal of medicinal chemistry [Eur J Med Chem] 2022 Jul 05; Vol. 237, pp. 114356. Date of Electronic Publication: 2022 Apr 21. |
DOI: | 10.1016/j.ejmech.2022.114356 |
Abstrakt: | Mutations in Fms-like tyrosine kinase 3 (FLT3) have been implicated in the pathogenesis of acute myeloid leukemia (AML) by affecting the proliferation and differentiation of hematopoietic stem and progenitor cells. Although several FLT3 inhibitors have been developed, the occurrence of secondary TKD mutations of FLT3 such FLT3/D835Y and FLT3/F691L lead to drug resistance and has become a key area of unmet medical needs. To overcome the obstacle of secondary TKD mutations, a new series of indirubin-3'-aminooxy-acetamide derivatives was discovered as potent and selective FLT3 and FLT3/D835Y inhibitors that were predicted to bind at the DFG-in active conformation of FLT3 in molecular docking studies. Through structure-activity relationship studies, the most optimized compound 13a was developed as a potent inhibitor at FLT3 and FLT3/D835Y with IC (Copyright © 2022 Elsevier Masson SAS. All rights reserved.) |
Databáze: | MEDLINE |
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