克服伊马替尼耐药的 BCR-ABL 突变体，具有新型脲苯并噻唑化学结构，具有强大和广谱的抗癌活性。

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

机构信息

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.

出版信息

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。