AI Summary
The article discusses the integration of amino acids into Bcr-Abl inhibitors for the design, synthesis, biological evaluation, and in silico studies. It addresses the challenge of point mutation resistance in the clinical treatment of CML. A library of compounds with tert-leucine or serine as linkers showed enhanced inhibition against Bcr-AblWT and Bcr-AblT315I kinases, with improved antiproliferative activity in leukemia cell assays. Compounds TL8, TL10, BS4, BS10, SR5, and SR11 exhibited potent inhibition activities against T315I mutant cells. Docking studies supported the rationale of using tert-leucine or serine as flexible linkers, and phenyipyridine with an amide sidechain favored the potency of these inhibitors. ADME prediction indicated a favorable safety profile for the tested compounds, suggesting potential for further optimization.
Bcr-Abl is successfully applied to drug discovery as the 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 HBM can achieve potent inhibition of Bcr-AblT315I. As continued, we further enriched the linker types by develoing a library of compound with tert-leucine or serine as linkers. Biological results show that these compounds have enhanced inhibition against Bcr-AblWT and Bcr-AblT315I kinases, as well as improved antiproliferative activity in leukemia cell assays compared to previously disclosed compounds. In particular, compounds TL8, TL10, BS4, BS10, SR5 and SR11 exhibited potent inhibition activities against Ba/F3 cells bearing T315I mutant. Additionally, compounds TL8, BS4 and SR5 effectively induced K562 cell apoptosis, arrest cell cycle at S or G2/M phase, and inhibited phosphorylation of Bcr-Abl and STAT5 in a dose dependent manner. Docking studies verified the rationality of tert-leucine or serine as flexibile linker, and indicated that phenyipyridine with amide sidechain favored the potency of these inhibitors. Moreover, ADME prediction suggested that 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 HBM, and compounds BS4 and SR5, especially TL8 can be used as starting points for further optimization.