Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology
Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology
复制标题
DOI：
10.1021/acs.jmedchem.8b01153
复制
发表时间：
2019-06-27
影响因子：
7.3
通讯作者：
Laufer, Stefan A.
中科院分区：
文献类型：
--
作者：
Gehringer, Matthias;Laufer, Stefan A.
靶向共价抑制物(TCI)旨在通过反应性基团(即所谓的弹头)结合保守程度较低的氨基酸。目前，靶向非催化半胱氨酸残基的丙烯酰胺和其他α，β-不饱和羰基化合物是TCI发展的主要策略。最近共价药物的兴起促使人们做出相当大的努力，以确定非催化半胱氨酸残基和其他氨基酸的共价可逆和不可逆结合的替代弹头的特征。这篇透视文章概述了最近用于靶向共价配体设计的弹头--除α，β-不饱和胺以外的弹头。还强调了尚未证明其在TCI开发中的效用的有前途的反应性基团。特别强调了反应性的讨论和案例研究在药物化学和化学生物学中的应用。
Targeted covalent inhibitors (TCIs) are designed to bind poorly conserved amino acids by means of reactive groups, the so-called warheads. Currently, targeting noncatalytic cysteine residues with acrylamides and other alpha,beta-unsaturated carbonyl compounds is the predominant strategy in TCI development. The recent ascent of covalent drugs has stimulated considerable efforts to characterize alternative warheads for the covalent-reversible and irreversible engagement of noncatalytic cysteine residues as well as other amino acids. This Perspective article provides an overview of warheads-beyond alpha,beta-unsaturated amides-recently used in the design of targeted covalent ligands. Promising reactive groups that have not yet demonstrated their utility in TCI development are also highlighted. Special emphasis is placed on the discussion of reactivity and of case studies illustrating applications in medicinal chemistry and chemical biology.