Targeting PAK1

Abstract

p21-Activated kinase 1 (PAK1) has attracted much attention as a potential therapeutic target due to its central role in many oncogenic signaling pathways, its frequent dysregulation in cancers and neurological disorders, and its tractability as a target for small-molecule inhibition. To date, several PAK1-targeting compounds have been developed as preclinical agents, including one that has been evaluated in a clinical trial. A series of ATP-competitive inhibitors, allosteric inhibitors and peptide inhibitors with distinct biochemical and pharmacokinetic properties represent useful laboratory tools for studies on the role of PAK1 in biology and in disease contexts, and could lead to promising therapeutic agents. Given the central role of PAK1 in vital signaling pathways, future clinical development of PAK1 inhibitors will require careful investigation of their safety and efficacy.

Keywords: cancer; protein–serine–threonine kinases; signaling; small molecules; therapeutics.

Figure 1. PAK1 structure

Organization of the PAK1 polypeptide chain highlighting sites of kinase phosphorylation. Numerals indicate residue numbers. PAK1 auto-regulatory region is in magenta, N-lobe of the catalytic domain is in green, and C-lobe is in blue. Proline-rich SH3-binding sites are shown as black bars. Phosphoinositide binding region enriched with basic residues is shown as srossed bar. Diagram of dimeric PAK1 (PDB ID: 1F3M). One PAK1 complex is colored as in (A), Thr 423 is labeled. The other one is presented as surface diagram. Residues 1–77 and 148–248 are omitted.

Figure 2. Co-crystal structures of ATP-competitive Pak inhibitors in complex with PAK1

Hydrogen-bonding interactions are shown as dotted red lines.

Figure 3. Pak inhibitors

Biochemical structures and selectivity profiles (inhibition ≥ 50% shown) of select Pak inhibitors. The molecule portions of ATP-competitive inhibitors rendered in red indicate the atoms participating in kinase hinge hydrogen bonding contacts. G-5555 (0.1 uM) screened aginst 235 kinases (Invitrogen) [49] FL172 (3 uM) screened against 246 kinases (Millipore) [31] PF-3758309 (1 uM) screened against 146 kinases at Pfizer, Invitrogen, and the University of Dundee.[32] AZ13705339 (0.1 uM) screened against 125 kinases (Invitrogen), PAK3 activity was not tested in this assay.[51] IPA-3 (10uM) screened against 214 kinases (Invitrogen) [53] NVS-PAK1-1 (10 uM) tested against 442 kinases (DiscoverX).[57] Illustration reproduced courtesy of Cell Signaling Technology, Inc. (www.cellsignal.com)