Identification and Optimization of Potent and Selective Inhibitors of PAK1
Edward J. Hennessy
The p21-activated kinases (PAKs) comprise a family of six serine/threonine protein kinases, divided into two subgroups based on sequence and structural homology: group I (PAKs 1-3) and group II (PAKs 4-6). Multiple PAK family members have been shown to interact directly or indirectly with a wide variety of other proteins, and as a result have been demonstrated to regulate a variety of cellular activities, such as cytoskeletal reorganization, cellular motility, and survival.
In recent years, emerging data has pointed to the role of PAK1 signaling in certain human cancers, suggesting that inhibitors of PAK1 kinase activity may have utility as antitumor agents. However, due to the relatively open and flexible ATP-binding site of this kinase, the identification of potent PAK1 inhibitors with high kinase selectivity and drug-like physical properties has remained a challenge. In this presentation, we will discuss our efforts towards this goal, highlighting the discovery and optimization of two structurally distinct chemical series of PAK1 inhibitors.