El-Damasy, Ashraf K. Jin, Heewon Seo, Seon Hee Bang, Eun-Kyoung Keum, Gyochang 2024-01-19T16:01:21Z 2024-01-19T16:01:21Z 2021-09-02 2020-12-01 0223-5234 https://pubs.kist.re.kr/handle/201004/117706 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-Abl(WT) with sub-micromolar IC50 values ranging 4.6e667 nM. In addition, certain derivatives exhibited promising potency over the clinically imatinib-resistant Bcr-Abl(T315I). Among the target molecules, compounds 9c, 9h and 10c stood as the most potent derivatives with IC50 values of 15.4 nM, 4.6 nM, and 25.8 nM, respectively, against BcrAblWT. Interestingly, 9h showed 2 folds and 3.6 times superior potency to the lead indazole II and 10c, respectively, against Bcr-Abl(T315I). Molecular docking of 9h pointed out its possibility to be a type II kinase inhibitor. Furthermore, all compounds, except 9b, showed highly potent antiproliferative activity against the Bcr-Abl positive leukemia K562 cell (MTT assay) surpassing the modest activity of lead indazole II. Moreover, the most potent members 9h and 10c exerted potent antileukemic activity against NCI leukemia panel, particularly K562 cell (SRB assay) with GI(50) less than 10 nM, being superior to the FDA approved drug imatinib. Further biochemical hERG and cellular toxicity, phosphorylation assay, and NanoBRET target engagement of 9h underscored its merits as a promising candidate for CML therapy. (C) 2020 Elsevier Masson SAS. All rights reserved. English ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER STRUCTURAL MECHANISM DRUG-RESISTANCE DISCOVERY IMATINIB MUTATION AP24534 MUTANT DOMAIN EXPRESSION BMS-354825 Design, synthesis, and biological evaluations of novel 3-amino-4-ethynyl indazole derivatives as Bcr-Abl kinase inhibitors with potent cellular antileukemic activity Article 10.1016/j.ejmech.2020.112710 1 EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v.207 EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 207 scie scopus 000591227400010 2-s2.0-85091070712 Chemistry, Medicinal Pharmacology & Pharmacy Article STRUCTURAL MECHANISM DRUG-RESISTANCE DISCOVERY IMATINIB MUTATION AP24534 MUTANT DOMAIN EXPRESSION BMS-354825 3-Aminoindazole Ethynyl linker Diarylamide Bcr-Abl(WT) Bcr-Abl(T315I) Imatinib resistance Antileukemic activity NanoBRET target engagement