2. Academic Validation
  3. Identification of a p21-activated kinase 1 (PAK1) inhibitor with 10-fold selectivity against PAK2

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.
Deidre M Johns 1,  Jason Olejniczak 2,  Anjali Babbar 2,  Christopher D Boone 3,  Ozgur Cakici 3,  Melinda Cheng 2,  Qing-Qing Cheng 2,  Alexey Dementiev 3,  Mariam Eick 2,  Nicky Ferdyan 2,  Eric Fontano 3,  Aaron Forman 2,  Ryan Kozlowski 2,  Szu-Wei Lee 2,  Shital Mehta 2,  Kayla Mowery 2,  Brion Murray 2,  Vivian Nguyen 2,  Andrea Olland 3,  Kim B Phan 2,  Lily Rivera 2,  Mark Sabat 2,  Paul Sprengeler 2,  Karthik Srinivasan 2,  Zhi Sun 2,  Robert K Suto 3,  Ty Wilkinson 2,  Chao Wang 2,  Ning Yu 2,  Meirong Xu 2,  Vikas Goel 2,  Gavin Hirst 2,  Siegfried Reich 2
Affiliations

Affiliations

  • 1 Turning Point Therapeutics, Inc. (a wholly owned subsidiary of Bristol Myers Squibb Company), 10628 Science Center Drive, Suite 200, San Diego, CA 92121, United States. Electronic address: deidre.johns@arrepath.com.
  • 2 Turning Point Therapeutics, Inc. (a wholly owned subsidiary of Bristol Myers Squibb Company), 10628 Science Center Drive, Suite 200, San Diego, CA 92121, United States.
  • 3 Schrödinger, Inc., 12 Michigan Drive, Natick, MA 01760, United States.
PMID: 40516764 DOI: 10.1016/j.bmcl.2025.130307
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.

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