| Autor: |
Liu, Yuying, Yang, Zeyu, Zhang, Jie, Guo, Na, Liu, Nanxin, Zhang, Qingqing, Dang, Xintao, Li, Yanchen, Zhang, Jie, Pan, Xiaoyan |
| Zdroj: |
MedChemComm; 2024, Vol. 15 Issue: 10 p3507-3528, 22p |
| Abstrakt: |
Bcr-Abl is successfully applied to drug discovery as a CML therapeutic target, but point mutation resistance has become a major challenge in the clinical treatment of CML. Our previous studies have shown that the introduction of amino acids as flexible linkers and heterocyclic structures as HBMs can achieve potent inhibition of Bcr-AblT315I. In continuation of these studies, we further enriched the linker types by developing a library of compounds with tert-leucine or serine as a linker. Biological results showed that these compounds exhibited enhanced inhibition against Bcr-AblWTand Bcr-AblT315Ikinases as well as improved antiproliferative activity in leukemia cell assays compared to previously disclosed compounds. In particular, compounds TL8, TL10, BS4, BS10, SR5and SR11exhibited potent inhibitory activities against Ba/F3 cells bearing a T315I mutant. Additionally, compounds TL8, BS4and SR5effectively induced K562 cell apoptosis, arrested the cell cycle at the S or G2/M phase, and inhibited the phosphorylation of Bcr-Abl and STAT5 in a dose-dependent manner. Docking studies verified the rationality of tert-leucine or serine as a flexible linker and indicated that phenylpyridine with an amide side chain favored the potency of these inhibitors. Moreover, ADME prediction suggested that the tested compounds had a favorable safety profile. Thus, tert-leucine or serine can be used as a promising class of flexible linkers for Bcr-Abl inhibitors with heterocyclic structures as HBMs, and compounds BS4, SR5, and especially TL8, can be used as starting points for further optimization. |
| Databáze: |
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