Technical University of Munich, 85354 Freising, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Structural Genomics Consortium, Goethe University Frankfurt, Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Strabe 15, 60438 Frankfurt am Main, Germany; Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strabe 9, 60438 Frankfurt, Germany; The Chemical Probes Portal, The Institute of Cancer Research, London SM2 5NG, UK.
Drug Discov Today. 2022 Feb;27(2):519-528. doi: 10.1016/j.drudis.2021.10.021. Epub 2021 Oct 30.
Selective chemical modulators are ideal tools to study the function of a protein. Yet, the poor ligandability of many proteins has hampered the development of specific chemical probes for numerous protein classes. Tools, such as covalent inhibitors and activity-based protein profiling, have enhanced our understanding of thus-far difficult-to-target proteins and have enabled correct assessment of the selectivity of small-molecule modulators. This also requires deeper knowledge of compound and target site reactivity, evaluation of binding to noncovalent targets and protein turnover. The availability of highly selective chemical probes, the evolution of activity-based probes, and the development of profiling methods will open a new era of drugging the undruggable proteome.
选择性化学调节剂是研究蛋白质功能的理想工具。然而，许多蛋白质的配体结合能力较差，这阻碍了针对众多蛋白质类别的特异性化学探针的开发。共价抑制剂和基于活性的蛋白质谱分析等工具增强了我们对迄今为止难以靶向的蛋白质的理解，并能够正确评估小分子调节剂的选择性。这还需要更深入地了解化合物和靶标部位的反应性，评估与非共价靶标的结合以及蛋白质周转率。高度选择性化学探针的可用性、基于活性探针的发展以及分析方法的开发将开启靶向不可成药蛋白质组的新时代。
