Deng Hongguang, Huang Min, Liu Hui, Zhang Hong, Liu Liang, Gao Bensheng, Li Xianlu, Li Jinbo, Niu Qun, Zhang Zhenwei, Luan Shenglin, Zhang Jingyi, Jing Yongkui, Liu Dan, Zhao Linxiang
Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China; Liaoning Key Laboratory of Targeting Drugs for Hematological Malignancies, Shenyang Pharmaceutical University, Shenyang 110016, China.
Bioorg Chem. 2022 Oct;127:106018. doi: 10.1016/j.bioorg.2022.106018. Epub 2022 Jul 12.
The B cell lymphoma protein 2 (Bcl-2) family proteins regulate cell apoptosis by participating in the endogenous apoptosis pathway. As an important anti-apoptotic protein, Myeloid cell leukemia 1 (Mcl-1) is overexpressed in a variety of tumor cells, and targeting this protein has been a promising strategy for cancer therapy. Herein, based on the 1H-indole-5-carboxylic acid structure previously discovered, we have developed a series of novel compounds with increased affinities and selectivity toward Mcl-1 through structure-based drug design. Among those compounds, 26 exerted relatively better affinity and selectivity for Mcl-1 with moderate inhibition in HL-60 cells. Mechanism studies showed that compound 26 could induce cancer cells apoptosis in an Mcl-1-dependent manner. It also exhibited good microsomal and plasma stability with acceptable pharmacokinetics profiles. Furthermore, treatment with target compound in a 4T1 xenograft mouse model significantly suppressed the tumor growth. Overall, the small molecule described herein represents a promising Mcl-1 inhibitor for further study.
B细胞淋巴瘤蛋白2（Bcl-2）家族蛋白通过参与内源性凋亡途径来调节细胞凋亡。髓样细胞白血病1（Mcl-1）作为一种重要的抗凋亡蛋白，在多种肿瘤细胞中过表达，靶向该蛋白一直是一种很有前景的癌症治疗策略。在此，基于先前发现的1H-吲哚-5-羧酸结构，我们通过基于结构的药物设计开发了一系列对Mcl-1具有更高亲和力和选择性的新型化合物。在这些化合物中，化合物26对Mcl-1表现出相对较好的亲和力和选择性，并在HL-60细胞中具有适度的抑制作用。机制研究表明，化合物26可以以Mcl-1依赖性方式诱导癌细胞凋亡。它还表现出良好的微粒体和血浆稳定性以及可接受的药代动力学特征。此外，在4T1异种移植小鼠模型中用目标化合物治疗可显著抑制肿瘤生长。总体而言，本文所述的小分子代表了一种有前景的用于进一步研究的Mcl-1抑制剂。
