Discovery of 3-((3-amino-1H-indazol-4-yl)ethynyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (AKE-72), a potent Pan-BCR-ABL inhibitor including the T315I gatekeeper resistant mutant

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 38; no. 1; p. 2228515
• Main Authors: El-Damasy, Ashraf K., Kim, Hyun Ji, Park, Jung Woo, Nam, Yunju, Hur, Wooyoung, Bang, Eun-Kyoung, Keum, Gyochang
• Format: Journal Article
• Language: English
• Published: ABINGDON Taylor & Francis 01.12.2023; Taylor & Francis Ltd; Taylor & Francis Group
• Subjects: ABL; Abl protein; ABLT315I; aminoindazole; Apoptosis; BCR protein; Benzamides - pharmacology; Biochemistry & Molecular Biology; Cell Line, Tumor; Cell Proliferation; Chemistry, Medicinal; Chronic myeloid leukaemia; Chronic myeloid leukemia; Design; diarylamides; Drug Resistance, Neoplasm; Fusion protein; Fusion Proteins, bcr-abl - genetics; Fusion Proteins, bcr-abl - metabolism; Humans; Imatinib; Imatinib Mesylate - pharmacology; Imatinib Mesylate - therapeutic use; Imatinib resistance; Indazoles - pharmacology; Kinases; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Life Sciences & Biomedicine; Mutation; Pharmaceutical sciences; Pharmacology & Pharmacy; Pharmacy; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Rapid Communication; Resistant mutant; Science & Technology; T315I; aminoindazole; IMATINIB-RESISTANT; Imatinib resistance; AP24534; BCR/ABL; Chronic myeloid leukaemia; ABL(T315I); TYROSINE KINASE INHIBITOR; diarylamides; CHRONIC MYELOID-LEUKEMIA; ABLT315I
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2023.2228515

BCR-ABL inhibition is an effective therapeutic approach for the treatment of chronic myeloid leukaemia (CML). Herein, we report the discovery of AKE-72 (5), a diarylamide 3-aminoindazole, as a potent pan-BCR-ABL inhibitor, including the imatinib-resistant mutant T315I. A focussed array of compounds 4a, 4b, and 5 has been designed based on our previously reported indazole I to improve its BCR-ABL T315I inhibitory activity. Replacing the morpholine moiety of I with the privileged tail (4-ethylpiperazin-1-yl)methyl afforded 5 (AKE-72) with IC 50 values of < 0.5 nM, and 9 nM against BCR-ABL WT and BCR-ABL T315I , respectively. Moreover, AKE-72 potently inhibited a panel of other clinically important mutants in single-digit nanomolar IC 50 values. AKE-72 elicited remarkable anti-leukemic activity against K-562 cell line (GI 50 < 10 nM, TGI = 154 nM). In addition, AKE-72 strongly inhibited the proliferation of Ba/F3 cells expressing native BCR-ABL or its T315I mutant. Overall, AKE-72 may serve as a promising candidate for the treatment of CML, including those harbouring T315I mutation.