The Development of Inhibitors to Target the Driving Functions of PAK1 in Cancer


  • David Harbaugh


The p21-activated kinases (PAKs) are a family of protein kinases that play major roles as downstream effectors of the small G-proteins Cdc42 and Rac1 under normal physiological conditions and disease states. Specifically, p21-activated kinase 1 (PAK1) has been shown to play a driving role in cancer development by impacting fundamental cellular functions, such as growth factor signaling and morphogenic processes. As a result, there is increased interest in developing small molecule inhibitors that modulate the activity of PAK1 as anti-cancer agents. This review evaluates the past ten years of research involving challenges related to efficacy, toxicity, and selectivity of the inhibitors that have prevented progress past preclinical development, informing the development of new strategies
to address these challenges.