Pogash Sarah, Fletcher Steven
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy 20 N. Pine St. Baltimore MD 21201 USA
University of Maryland Marlene & Stewart Greenebaum Cancer Centre 20 S. Greene St. Baltimore MD 21201 USA.
RSC Med Chem. 2025 Apr 15. doi: 10.1039/d5md00095e.
Overexpression and activation of kinases often results in cancer initiation and progression through both catalytic and non-catalytic functions that promote rapid proliferation, growth, survival, and metastasis of cells. Catalytic functions are effectively blocked with the use of ATP-competitive inhibitors, however drug-resistant mutations are emerging all the time. Further, single-agent ATP-competitive inhibitors sometimes fail to eliminate oncogenic properties of the targeted kinase, likely due to (non-targeted) non-catalytic functions that are maintained. Non-catalytic functions - such as scaffolding roles, where the kinase may interact with other proteins to coordinate cellular activities or protect them from degradation by the proteasome - may be targeted through the development of protein-protein interaction (PPI) inhibitors, although this is a highly challenging endeavour. To overcome the limitations of classical (ATP-competitive) inhibitors (and circumvent the formidable feat required in the development of PPI inhibitors), which operate through "occupancy-driven" pharmacology, targeted protein degradation, as showcased by proteolysis targeting chimeras (PROTACs), is fast becoming a highly sought-after goal for a large plethora of protein targets, and is governed by "event-driven" pharmacology. Because PROTACs result in the degradation of the protein of interest, these compounds are predicted to both catalytic and non-catalytic functions of a targeted kinase. Herein, we focus on the development of PROTACs that target (i) the scaffolding roles of focal adhesion kinase (FAK) that are associated with the formation of signaling units involved in migration and invasion events and (ii) the scaffolding roles of Aurora-A kinase (AURKA), which play a role in the protection of MYC proteins from proteasomal degradation.
激酶的过表达和激活通常通过促进细胞快速增殖、生长、存活和转移的催化和非催化功能导致癌症的起始和进展。使用ATP竞争性抑制剂可有效阻断催化功能，然而耐药性突变一直在出现。此外，单药ATP竞争性抑制剂有时无法消除靶向激酶的致癌特性，这可能是由于所维持的（非靶向）非催化功能。非催化功能——例如支架作用，激酶可能在其中与其他蛋白质相互作用以协调细胞活动或保护它们不被蛋白酶体降解——可以通过开发蛋白质-蛋白质相互作用（PPI）抑制剂来靶向，尽管这是一项极具挑战性的工作。为了克服经典（ATP竞争性）抑制剂的局限性（并规避开发PPI抑制剂所需的艰巨任务），后者通过“占据驱动”药理学发挥作用，靶向蛋白质降解，如蛋白酶体靶向嵌合体（PROTAC）所展示的那样，正迅速成为众多蛋白质靶点备受追捧的目标，并且由“事件驱动”药理学所支配。由于PROTAC导致目标蛋白的降解，预计这些化合物对靶向激酶的催化和非催化功能均有效。在此，我们专注于PROTAC的开发，这些PROTAC靶向（i）粘着斑激酶（FAK）的支架作用，其与参与迁移和侵袭事件的信号单元形成相关；（ii）极光激酶A（AURKA）的支架作用，其在保护MYC蛋白不被蛋白酶体降解中发挥作用。
