Design, synthesis, and biological evaluations of novel 3-amino-4-ethynyl indazole derivatives as Bcr-Abl kinase inhibitors with potent cellular antileukemic activity
- Design, synthesis, and biological evaluations of novel 3-amino-4-ethynyl indazole derivatives as Bcr-Abl kinase inhibitors with potent cellular antileukemic activity
- 서선희; 금교창; 방은경; Ashraf Kareem Awad Mohammed Eldamasy; 진희원
- 3-Aminoindazole; Ethynyl linker; Diarylamide; Bcr-AblWT; Bcr-AblT315I; Imatinib resistance; Antileukemic activity; NanoBRET target engagement
- Issue Date
- European journal of medicinal chemistry
- VOL 207, 112710
- Breakpoint cluster region-Abelson (Bcr-Abl) kinase is a key driver in the pathophysiology of chronic myelogenous leukemia (CML). Broadening the chemical diversity of Bcr-Abl kinase inhibitors with novel chemical entities possessing favorable target potency and cellular efficacy is a current medical demand for CML treatment. In this respect, a new series of ethynyl bearing 3-aminoindazole based Bcr-Abl inhibitors has been designed, synthesized, and biologically evaluated. The target compounds were designed based on introducing the key structural features of ponatinib, alkyne spacer and diarylamide, into the previously reported indazole II to improve its Bcr-Abl inhibitory activity and overcome its poor cellular potency. All target compounds elicited potent activity against Bcr-AblWT with sub-micromolar IC50 values ranging 4.6？667 nM. In addition, certain derivatives exhibited promising potency over the clinically imatinib-resistant Bcr-AblT315I. Among the target molecules, compounds 9c,
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