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.
In: Journal of enzyme inhibition and medicinal chemistry, Jg. 38 (2023-12-01), Heft 1, S. 2228515
Online
academicJournal
Zugriff:
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.
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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.
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Autor/in / Beteiligte Person: | El-Damasy, AK ; Kim, HJ ; Park, JW ; Nam, Y ; Hur, W ; Bang, EK ; Keum, G |
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Zeitschrift: | Journal of enzyme inhibition and medicinal chemistry, Jg. 38 (2023-12-01), Heft 1, S. 2228515 |
Veröffentlichung: | Basingstoke, UK : Taylor & Francis, c2002-, 2023 |
Medientyp: | academicJournal |
ISSN: | 1475-6374 (electronic) |
DOI: | 10.1080/14756366.2023.2228515 |
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