Substituted indole Mcl-1 inhibitors: a patent evaluation (WO2015148854A1)
Substituted indole Mcl-1 inhibitors: a patent evaluation (WO2015148854A1)
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取代吲哚 Mcl-1 抑制剂：专利评估 (WO2015148854A1)
DOI：
10.1080/13543776.2016.1240786
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发表时间：
2016
影响因子：
6.6
通讯作者：
Zhang Zhichao
中科院分区：
文献类型：
--
作者：
Song Ting;Wang Ziqian;Zhang Zhichao
髓样细胞白血病1（Myeloid Cell Leukemia 1，Mcl-1）蛋白是Bcl-2家族的一个抗凋亡蛋白，在多种癌症的发生和维持中起着关键作用，被列为人类癌症的十大病理因素之一。该评价中描述的专利（W 02015148854 A1）要求保护用于治疗疾病和病症（例如，癌症），其特征在于Mcl-1蛋白的过度表达或失调。多种2位取代基将本专利中要求保护的吲哚Mcl-1抑制剂与AbbVie Inc.的另外两个专利区分开来。（W 02008131000 A2和W 02008130970 A1）。它们在体外表现出低纳摩尔结合亲和力和超过Bcl-2和Bcl-xLin 100倍的选择性，以及对一组肿瘤细胞系的低微摩尔杀伤能力。此外，该专利中的化合物揭示了选择性Mcl-1抑制剂的结构基础可能不完全依赖于5个已知的结合热点，并且Mcl-1蛋白的构象柔性可能有助于结合特异性。
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-xLin 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.