Leibniz Forschungsinstitut für Molekulare Pharmakologie, Robert-Rössle-Straße 10, 13125, Berlin, Germany; Humboldt-Universität zu Berlin, Institut für Chemie, Brook-Taylor-Straße 2, 12489, Berlin, Germany.
Adv Biol Regul. 2022 Jan;83:100836. doi: 10.1016/j.jbior.2021.100836. Epub 2021 Nov 9.
Inositol poly- and pyrophosphates (InsPs and PP-InsPs) are a group of central eukaryotic metabolites and signaling molecules. Due to the diverse cellular functions and widespread diseases InsPs and PP-InsPs are associated with, pharmacological targeting of the kinases involved in their biosynthesis has become a significant research interest in the last decade. In particular, the development of inhibitors for inositol hexakisphosphate kinases (IP6Ks) has leaped forward, while other inositol phosphate kinases have received scant attention. This review summarizes the efforts undertaken so far for discovering potent and selective inhibitors for this diverse group of small molecule kinases. The benefits of pharmacological inhibition are highlighted, given the multiple kinase-independent functions of inositol phosphate kinases. The distinct structural families of InsP and PP-InsP kinases are presented, and we discuss how compound availability for different inositol phosphate kinase families varies drastically. Lead compound discovery and optimization for the inositol kinases would benefit from detailed structural information on the ATP-binding sites of these kinases, as well as reliable biochemical and cellular read-outs to monitor inositol phosphate kinase activity in complex settings. Efforts to further tune well-established inhibitors, while simultaneously reviving tool compound development for the more neglected kinases from this family are indisputably worthwhile, considering the large potential therapeutic benefits.
肌醇多聚磷酸盐和焦磷酸盐（InsPs 和 PP-InsPs）是一组重要的真核代谢物和信号分子。由于 InsPs 和 PP-InsPs 与多种细胞功能和广泛的疾病相关，因此涉及它们生物合成的激酶的药理学靶向已成为过去十年中的重要研究热点。特别是，肌醇六磷酸激酶（IP6Ks）抑制剂的开发取得了飞跃性的进展，而其他肌醇磷酸盐激酶则受到了较少的关注。本文综述了迄今为止为发现这种多样化的小分子激酶的有效且选择性抑制剂所做的努力。鉴于肌醇磷酸盐激酶具有多种激酶非依赖性的功能，强调了药理学抑制的益处。本文介绍了不同的 InsP 和 PP-InsP 激酶结构家族，并讨论了不同肌醇磷酸盐激酶家族的化合物可用性有何显著差异。如果能详细了解这些激酶的 ATP 结合位点的结构信息，并获得可靠的生化和细胞检测方法来监测复杂环境中的肌醇磷酸盐激酶活性，那么对于肌醇激酶的先导化合物发现和优化将大有裨益。进一步调整已确立的抑制剂，同时恢复该家族中被忽视的激酶的工具化合物开发，考虑到巨大的潜在治疗益处，这无疑是值得的。
