Xia Meng, Li Ziteng, Jiang Hanrui, Li Yuanqing, Hu Linghao, He Yongchang, Huang Siqi, Tang Lei, Luo Cheng, Gu Shuangxi, Ding Hong, Wang Mingliang
State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmacy, Guizhou Medical University, Guiyang, 550004, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
Eur J Med Chem. 2025 Apr 15;288:117378. doi: 10.1016/j.ejmech.2025.117378. Epub 2025 Feb 10.
Triple-negative breast cancer (TNBC) is widely recognized as the most aggressive subtype of breast cancer, and treatment options for patients with TNBC remain highly limited. Recently, cyclin-dependent kinases 12/13 (CDK12/13) have been identified as promising therapeutic targets for TNBC. In our study, we report the design and synthesis of novel imidazo[1,2-b]pyrazine-based covalent inhibitors of CDK12/13, which exhibit potent inhibitory activity against TNBC cells. Among these compounds, compound 24 emerged as the most potent inhibitor, with CDK12 IC of 15.5 nM and CDK13 IC of 12.2 nM. Compound 24 forms a covalent bond with Cys1039 of CDK12 and effectively suppresses the proliferation of TNBC cell lines MDA-MB-231 and MDA-MB-468, with EC values of 5.0 nM and 6.0 nM, respectively. Compound 24 demonstrated superior efficacy to the currently known CDK12/13 covalent inhibitor, THZ531. These findings suggest compound 24 may be a promising lead for developing CDK12/13-targeted therapies for treating TNBC.
三阴性乳腺癌（TNBC）被广泛认为是乳腺癌中最具侵袭性的亚型，TNBC患者的治疗选择仍然非常有限。最近，细胞周期蛋白依赖性激酶12/13（CDK12/13）已被确定为TNBC有前景的治疗靶点。在我们的研究中，我们报道了新型咪唑并[1,2-b]吡嗪基CDK12/13共价抑制剂的设计与合成，这些抑制剂对TNBC细胞表现出强效抑制活性。在这些化合物中，化合物24成为最有效的抑制剂，CDK12的IC为15.5 nM，CDK13的IC为12.2 nM。化合物24与CDK12的Cys1039形成共价键，并有效抑制TNBC细胞系MDA-MB-231和MDA-MB-468的增殖，EC值分别为5.0 nM和6.0 nM。化合物24表现出优于目前已知的CDK12/13共价抑制剂THZ531的疗效。这些发现表明化合物24可能是开发用于治疗TNBC的CDK12/13靶向疗法的有前景的先导化合物。
