基于结构的强效 Bcl-2/Bcl-xL 抑制剂的设计及其在体内的抗肿瘤活性。
Structure-based design of potent Bcl-2/Bcl-xL inhibitors with strong in vivo antitumor activity.
机构信息
Comprehensive Cancer Center and Departments of Internal Medicine, Pharmacology and Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109-0934, USA.
出版信息
J Med Chem. 2012 Jul 12;55(13):6149-61. doi: 10.1021/jm300608w. Epub 2012 Jul 2.
Abstract
Bcl-2 and Bcl-xL are key apoptosis regulators and attractive cancer therapeutic targets. We have designed and optimized a class of small-molecule inhibitors of Bcl-2 and Bcl-xL containing a 4,5-diphenyl-1H-pyrrole-3-carboxylic acid core structure. A 1.4 Å resolution crystal structure of a lead compound, 12, complexed with Bcl-xL has provided a basis for our optimization. The most potent compounds, 14 and 15, bind to Bcl-2 and Bcl-xL with subnanomolar K(i) values and are potent antagonists of Bcl-2 and Bcl-xL in functional assays. Compounds 14 and 15 inhibit cell growth with low nanomolar IC(50) values in multiple small-cell lung cancer cell lines and induce robust apoptosis in cancer cells at concentrations as low as 10 nM. Compound 14 also achieves strong antitumor activity in an animal model of human cancer.
摘要
Bcl-2 和 Bcl-xL 是凋亡的关键调节因子，也是有吸引力的癌症治疗靶点。我们设计并优化了一类含有 4,5-二苯基-1H-吡咯-3-羧酸核心结构的 Bcl-2 和 Bcl-xL 的小分子抑制剂。一个先导化合物 12 与 Bcl-xL 形成的 1.4 Å 分辨率晶体结构为我们的优化提供了基础。最有效的化合物 14 和 15 以亚纳摩尔的 K(i)值与 Bcl-2 和 Bcl-xL 结合，并且在功能测定中是 Bcl-2 和 Bcl-xL 的有效拮抗剂。化合物 14 和 15 在多种小细胞肺癌细胞系中以低纳摩尔的 IC(50)值抑制细胞生长，并在低至 10 nM 的浓度下诱导癌细胞强烈凋亡。化合物 14 在人类癌症的动物模型中也表现出很强的抗肿瘤活性。
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