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论文类型：期刊论文

发表时间：2016-11-01

发表刊物：EXPERT OPINION ON THERAPEUTIC PATENTS

收录刊物：SCIE、PubMed

卷号：26

期号：11

页面范围：1227-1238

ISSN号：1354-3776

关键字：Apoptosis; cancer; Mcl-1; Bcl-2; small-molecule inhibitors of Mcl-1; pan and selective

摘要：The myeloid cell leukemia 1 (Mcl-1) protein, an anti-apoptotic member of Bcl-2 family, plays a critical role in the development and maintenance of many cancers and is listed in the 'top ten' pathological factors across the diversity of human cancers. The patent described in this evaluation (WO2015148854A1) claimed substituted indole Mcl-1 inhibitors for the treatment of diseases and conditions (e.g., cancer) characterized by the over-expression or dysregulation of Mcl-1 proteins. A variety of 2-position substituents distinguished indole Mcl-1 inhibitors claimed in this patent from another two patents by AbbVie Inc. (WO2008131000A2 and WO2008130970A1). They exhibited low-nanomolar binding affinities and >100-fold selectivity over Bcl-2 and Bcl-xL in vitro, and low-micromolar killing abilities against a panel of tumour cell lines. Moreover, the compounds in this patent revealed that the structural basis for selective Mcl-1 inhibitors may not completely depend on the 5 known binding hot-spots, and conformational flexibility of Mcl-1 protein could contribute to the binding specificity.