Identification of a p21-activated kinase 1 (PAK1) inhibitor with 10-fold selectivity against PAK2

Bioorg Med Chem Lett. 2025 Nov 1:127:130307. doi: 10.1016/j.bmcl.2025.130307. Epub 2025 Jun 12.

Abstract

The p21-activated kinases (PAKs) are noted for their role in cytoskeletal organization, cellular morphogenesis, and pro-survival signaling. PAK1 is of particular interest due to its role in tumorigenesis, being amplified in multiple cancers (the most prevalent being breast, ovarian, and melanoma cancers). PAK2 is closely related to PAK1 in structure but is associated with cardiotoxicity. A structure-based design effort targeting a PAK1 (over PAK2) selective small molecule inhibitor is detailed herein. We report here the first crystal structure of PAK2 and use this crystal structure to design a PAK1 inhibitor with ten-fold selectivity over PAK2.

Keywords: Kinase; Medicinal chemistry; Oncology; PAK; Structure-based drug discovery; cancer.

MeSH terms

  • Crystallography, X-Ray
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors* / chemical synthesis
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Structure-Activity Relationship
  • p21-Activated Kinases* / antagonists & inhibitors
  • p21-Activated Kinases* / metabolism

Substances

  • p21-Activated Kinases
  • Protein Kinase Inhibitors
  • PAK1 protein, human
  • PAK2 protein, human