Fragment-Based Design, Synthesis, and Biological Evaluation of 1-Substituted-indole-2-carboxylic Acids as Selective Mcl-1 Inhibitors
发布时间：2019-03-12
点击次数：
- 论文类型：
- 期刊论文
- 发表时间：
- 2017-01-01
- 发表刊物：
- ARCHIV DER PHARMAZIE
- 收录刊物：
- Scopus、PubMed、SCIE
- 文献类型：
- J
- 卷号：
- 350
- 期号：
- 1
- ISSN号：
- 0365-6233
- 关键字：
- Fragment-based drug design; Ligand efficiency; Mcl-1 inhibitor; p1 pocket; Selective
- 摘要：
- Based on a known selective Mcl-1 inhibitor, 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylic acid, we applied a fragment-based approach to obtain new molecules that extended into the p1 pocket of the BH3 groove and then exhibited binding selectivity for the Mcl-1 over the Bcl-2 protein. After we deconstructed the 1H-indole-2-carboxylic acid from the parental molecule, a benzenesulfonyl was substituted at the 1-position to adopt a geometry preferred for accessing the p1 pocket according to the binding mode of the parental molecule identified by X-ray crystallography. A linear relationship between the free energy of ligand binding (Delta G) and the count of non-hydrogen heavy atoms (HAC) was maintained during the molecular growing to occupy the p1 pocket. Finally, we not only obtained compound 12 with a 7.5-fold selectivity to Mcl-1 (K-i = 0.48 mu M by fluorescence polarization) over Bcl-2 (K-i = 3.6 mu M), but also provided evidence that additional occupation of the p1 pocket is more favorable for Mcl-1 than for Bcl-2 binding, and contributes more to Mcl-1 inhibition than occupation of the p2 pocket. Compound 12 exhibited a selective killing ability on Mcl-1-dependent cancer cells.
- 第一作者
- Wang, Ziqian
- 合写作者
- Zhang, Zhichao,Liu, Lu,Fan, Yudan,Wang, Anhui,Song, Ting,Guo, Zongwei,Xu, Wenjie
- 通讯作者
- Zhang, ZC (reprint author), Dalian Univ Technol, Sch Chem, State Key Lab Fine Chem, Dalian 116012, Peoples R China.