Center for Brain Technology, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.
Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
J Enzyme Inhib Med Chem. 2023 Dec;38(1):2189097. doi: 10.1080/14756366.2023.2189097.
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 as a potent pan-BCR-ABL inhibitor against imatinib-resistant mutants, particularly T315I. A concise array of six compounds - was designed based on our previously reported benzothiazole lead to improve its BCR-ABL inhibitory activity. Replacing the 6-oxypicolinamide moiety of with -methoxyphenyl and changing the propyl spacer with phenyl afforded and with IC values of 2.0 and 0.65 nM against BCR-ABL, respectively. showed superior anticancer potency to imatinib against multiple cancer cells (NCI), including leukaemia K-562. The obtained outcomes offer as a promising candidate for the treatment of CML and other types of cancer.
针对致癌激酶 BCR-ABL 的激酶抑制剂的设计构成了治疗慢性髓性白血病 (CML) 的有前途的范例。然而，伊马替尼（FDA 批准的第一种用于 CML 的靶向治疗药物）的疗效受到耐药性的限制。在此，我们报告了 2-甲氧基苯基脲苯并噻唑作为针对伊马替尼耐药突变体，特别是 T315I 的有效泛 BCR-ABL 抑制剂的鉴定。基于我们之前报道的苯并噻唑先导物，设计了一个简洁的六元化合物系列，以提高其 BCR-ABL 抑制活性。用 -甲氧基苯基取代 中的 6-氧代吡啶酰胺部分，并将丙基间隔基改为苯基，得到化合物 和 ，它们对 BCR-ABL 的 IC 值分别为 2.0 和 0.65 nM。 显示出比伊马替尼对多种癌细胞（NCI），包括白血病 K-562 更强的抗癌活性。获得的结果为治疗 CML 和其他类型的癌症提供了有前途的候选药物 。
