Clinical candidates modulating protein-protein interactions: The fragment-based experience

被引：19
|
作者：
Valenti, Dario [1 ,2 ,3 ]
Hristeva, Stanimira [1 ]
Tzalis, Dimitrios [1 ]
Ottmann, Christian [2 ,3 ,4 ]
机构：
[1] Taros Chem GmbH & Co KG, Med Chem, Emil Figge Str 76a, D-44227 Dortmund, Germany
[2] Tech Univ Eindhoven, Dept Biomed Engn, Den Dolech 2, NL-5612 AZ Eindhoven, Netherlands
[3] Tech Univ Eindhoven, Inst Complex Mol Syst, Den Dolech 2, NL-5612 AZ Eindhoven, Netherlands
[4] Univ Duisburg Essen, Dept Chem, Univ Str 7, D-45117 Essen, Germany
来源：
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 167卷
基金：
欧盟地平线“2020”;
关键词：
Protein-protein interaction; Modulator; Fragment-based; Clinical candidate; BH3 MIMETIC ABT-737; SMALL-MOLECULE INHIBITOR; BCL-2 FAMILY PROTEINS; NF-KAPPA-B; DRUG DISCOVERY; BET FAMILY; PHASE-I; SELECTIVE-INHIBITION; STRUCTURAL BIOLOGY; LEAD SERIES;
D O I：
10.1016/j.ejmech.2019.01.084
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Protein-protein interactions (PPIs) cover a very wide range of biological functions and consequently have become one of the favourite targets for new therapeutic strategies. PPIs are strongly characterised by an intricate and dynamic network of surface interactions occurring between two or more proteins. Because of the complexity of these interactions, many strategies have been applied with the aim to find selective modulators for a specific protein-protein complex. During the last decade, fragment-based approaches have served many drug discovery programs with an impressive increment of contributions, gaining a remarkable role in PPIs modulators' development. In this review, we detail the successful fragment-to clinical candidate evolutions related to PPI modulation. An overview on the physico-chemical properties of both fragment hits and lead compounds will be presented together with a statistical analysis of their distribution. (C) 2019 Elsevier Masson SAS. All rights reserved.
引用
收藏
页码：76 / 95
页数：20
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