Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, U.S.A.
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, U.S.A.
Biochem J. 2023 Aug 30;480(16):1331-1363. doi: 10.1042/BCJ20220217.
There are over 500 human kinases ranging from very well-studied to almost completely ignored. Kinases are tractable and implicated in many diseases, making them ideal targets for medicinal chemistry campaigns, but is it possible to discover a drug for each individual kinase? For every human kinase, we gathered data on their citation count, availability of chemical probes, approved and investigational drugs, PDB structures, and biochemical and cellular assays. Analysis of these factors highlights which kinase groups have a wealth of information available, and which groups still have room for progress. The data suggest a disproportionate focus on the more well characterized kinases while much of the kinome remains comparatively understudied. It is noteworthy that tool compounds for understudied kinases have already been developed, and there is still untapped potential for further development in this chemical space. Finally, this review discusses many of the different strategies employed to generate selectivity between kinases. Given the large volume of information available and the progress made over the past 20 years when it comes to drugging kinases, we believe it is possible to develop a tool compound for every human kinase. We hope this review will prove to be both a useful resource as well as inspire the discovery of a tool for every kinase.
有超过 500 个人类激酶，从研究得非常透彻的到几乎完全被忽视的都有。激酶是可处理的，并且与许多疾病有关，这使它们成为药物化学研究的理想目标，但是否有可能为每个单独的激酶发现一种药物呢？对于每一个人类激酶，我们收集了关于它们的引文数量、化学探针的可用性、已批准和正在研究的药物、PDB 结构以及生化和细胞测定的数据。对这些因素的分析突出了哪些激酶组有大量可用的信息，以及哪些组仍有进展的空间。数据表明，人们过分关注那些特征更为明显的激酶，而激酶组的很大一部分仍然相对研究不足。值得注意的是，针对研究不足的激酶已经开发出了工具化合物，而且在这个化学空间中仍然有进一步开发的潜力。最后，这篇综述讨论了许多用于在激酶之间产生选择性的不同策略。鉴于目前可获得的大量信息以及过去 20 年来在激酶药物方面取得的进展，我们相信有可能为每个人类激酶开发出一种工具化合物。我们希望这篇综述不仅能成为一个有用的资源，还能激发为每个激酶发现工具化合物的灵感。
