a Department of Pharmacy , University of Pisa , Pisa , Italy.
Expert Opin Ther Pat. 2019 Apr;29(4):271-282. doi: 10.1080/13543776.2019.1597852. Epub 2019 Mar 29.
3-Phosphoinositide-dependent kinase 1 (PDK1), the 'master kinase of the AGC protein kinase family', plays a key role in cancer development and progression. Although it has been rather overlooked, in the last decades a growing number of molecules have been developed to effectively modulate the PDK1 enzyme.
This review collects different PDK1 inhibitors patented from October 2014 to December 2018. The molecules have been classified on the basis of the chemical structure/type of inhibition, and for each general structure, examples have been discussed in extenso.
The role of PDK1 in cancer development and progression as well as in metastasis formation and in chemoresistance has been confirmed by many studies. Therefore, the pharmaceutical discovery in both public and private institutions is still ongoing despite the plentiful molecules already published. The majority of the new molecules synthetized interact with binding sites different from the ATP binding site (i.e. PIF pocket or DFG-out conformation). However, many researchers are still looking for innovative PDK1 modulation strategy such as combination of well-known inhibitory agents or multitarget ligands, aiming to block, together with PDK1, other different critical players in the wide panorama of proteins involved in tumor pathways.
3-磷酸肌醇依赖性激酶 1（PDK1）是“AGC 蛋白激酶家族的主激酶”，在癌症的发生和发展中起着关键作用。尽管它一直被忽视，但在过去的几十年中，已经开发出越来越多的分子来有效地调节 PDK1 酶。
本文收集了 2014 年 10 月至 2018 年 12 月期间获得专利的不同 PDK1 抑制剂。这些分子是根据化学结构/抑制类型进行分类的，对于每种通用结构，都进行了详细的讨论。
许多研究已经证实，PDK1 在癌症的发生和发展以及转移形成和化疗耐药性中起作用。因此，尽管已经发表了大量的分子，但公共和私营机构的药物发现仍在继续。大多数新合成的分子与 ATP 结合位点（即 PIF 口袋或 DFG-out 构象）不同的结合位点相互作用。然而，许多研究人员仍在寻找创新的 PDK1 调节策略，例如将知名抑制剂或多靶点配体联合使用，旨在与 PDK1 一起阻断肿瘤途径中涉及的广泛蛋白质中其他不同的关键参与者。
