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

  • J Enzyme Inhib Med Chem. 2023 Dec;38(1):2189097. doi: 10.1080/14756366.2023.2189097.
Ashraf K El-Damasy  1  2 ,  Heewon Jin  1 ,  Jung Woo Park  3 ,  Hyun Ji Kim  1 ,  Hanan Khojah  4 ,  Seon Hee Seo  5 ,  Ju-Hyeon Lee  1 ,  Eun-Kyoung Bang  1 ,  Gyochang Keum  1  6
Affiliations
  • 1. Center for Brain Technology, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.
  • 2. Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
  • 3. Center for Supercomputing Applications, Div. of National Supercomputing R&D, Korea Institute of Science and Technology Information, Daejeon, Republic of Korea.
  • 4. Department of Pharmacognosy, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia.
  • 5. Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.
  • 6. Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology (UST), Seoul, Republic of Korea.
PMID: 36927348 DOI: 10.1080/14756366.2023.2189097
Abstract

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 2a-f 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.

Keywords
BCR-ABLT315I; CML; Ureidobenzothiazoles; anticancer activity; imatinib resistance.
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