Department of Biochemistry , Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall , Nashville , Tennessee 37232-0146 , United States.
J Med Chem. 2018 Mar 22;61(6):2410-2421. doi: 10.1021/acs.jmedchem.7b01155. Epub 2018 Mar 9.
Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family of proteins, has emerged as an attractive target for cancer therapy. Mcl-1 upregulation is often found in many human cancers and is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here, we describe a series of potent and selective tricyclic indole diazepinone Mcl-1 inhibitors that were discovered and further optimized using structure-based design. These compounds exhibit picomolar binding affinity and mechanism-based cellular efficacy, including growth inhibition and caspase induction in Mcl-1-sensitive cells. Thus, they represent useful compounds to study the implication of Mcl-1 inhibition in cancer and serve as potentially useful starting points toward the discovery of anti-Mcl-1 therapeutics.
髓系细胞白血病 1（Mcl-1）是 Bcl-2 家族蛋白中的一种抗凋亡成员，已成为癌症治疗的一个有吸引力的靶点。Mcl-1 的上调通常在许多人类癌症中发现，与高肿瘤分级、不良预后和对化疗的耐药性有关。在这里，我们描述了一系列有效的、选择性的三环吲哚二氮酮 Mcl-1 抑制剂，这些抑制剂是使用基于结构的设计发现并进一步优化的。这些化合物表现出皮摩尔结合亲和力和基于机制的细胞功效，包括在 Mcl-1 敏感细胞中抑制生长和诱导半胱天冬酶。因此，它们代表了研究 Mcl-1 抑制在癌症中的意义的有用化合物，并作为发现抗 Mcl-1 治疗药物的潜在有用起点。
