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

Abstract

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 IC₅₀ 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 IC₅₀ values. AKE-72 elicited remarkable anti-leukemic activity against K-562 cell line (GI₅₀ < 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.

GRAPHICAL ABSTRACT

Keywords:

• Chronic myeloid leukaemia
• aminoindazole
• diarylamides
• ABL^T315I
• Imatinib resistance

Acknowledgements

The authors express our appreciation to the National Cancer Institute (NCI, Bethesda, Maryland, USA) for performing the in vitro anticancer evaluation of the new compounds.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This research was supported by the National Research Council of Science & Technology (NST) grant by the Korean government (MSIT) [No. CAP-20–01-KRIBB], the Institutional Program grant by the Korea Institute of Science and Technology [2E32212]. A.K. El-Damasy was supported by the Korea Research Fellowship Program grant through NRF funded by the Ministry of Science and ICT [2019H1D3A1A01070882]. This research was also supported by the Korea Institute of Science and Technology Information (KISTI) Institutional Program.