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Overcoming the imatinib-resistant BCR-ABL mutants with new ureidobenzothiazole chemotypes endowed with potent and broad-spectrum anticancer activity

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posted on 2023-03-17, 09:40 authored by Ashraf K. El-Damasy, Heewon Jin, Jung Woo Park, Hyun Ji Kim, Hanan Khojah, Seon Hee Seo, Ju-Hyeon Lee, Eun-Kyoung Bang, Gyochang Keum

The design of kinase inhibitors targeting the oncogenic kinase BCR-ABL constitutes a promising paradigm for treating chronic myeloid leukaemia (CML). Nevertheless, the efficacy of imatinib, the first FDA-approved targeted therapy for CML, is curbed by the emergence of resistance. Herein, we report the identification of the 2-methoxyphenyl ureidobenzothiazole AK-HW-90 (2b) as a potent pan-BCR-ABL inhibitor against imatinib-resistant mutants, particularly T315I. A concise array of six compounds 2af was designed based on our previously reported benzothiazole lead AKE-5l to improve its BCR-ABLT315I inhibitory activity. Replacing the 6-oxypicolinamide moiety of AKE-5l with o-methoxyphenyl and changing the propyl spacer with phenyl afforded 2a and AK-HW-90 (2b) with IC50 values of 2.0 and 0.65 nM against BCR-ABLT315I, respectively. AK-HW-90 showed superior anticancer potency to imatinib against multiple cancer cells (NCI), including leukaemia K-562. The obtained outcomes offer AK-HW-90 as a promising candidate for the treatment of CML and other types of cancer.

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 is supported by the Korea Research Fellowship (KRF) Program grant through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT [No. 2019H1D3A1A01070882]. This research was also supported by the Korea Institute of Science and Technology Information (KISTI) Institutional Program. We would like to express our appreciation to the National Cancer Institute (NCI, Bethesda, Maryland, USA) for performing the in vitro anticancer evaluation of the new compounds.

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