9D4Y

Structure of PAK1 in complex with compound 31

This is a non-PDB format compatible entry.

Summary for 9D4Y

• Entry DOI: 10.2210/pdb9d4y/pdb
• Descriptor: Serine/threonine-protein kinase PAK 1, N~2~-{[(1R,3R,4S)-4-amino-3-(3-chlorophenyl)cyclohexyl]methyl}-N~4~-(5-cyclopropyl-1,3-thiazol-2-yl)pyrimidine-2,4-diamine (3 entities in total)
• Functional Keywords: serine/threonine-protein kinase, transferase, inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 67482.58

Authors

Fontano, E.,Suto, R.K.,Olland, A.M. (deposition date: 2024-08-13, release date: 2025-04-02, Last modification date: 2025-07-16)

Primary citation

Johns, D.M.,Olejniczak, J.,Babbar, A.,Boone, C.D.,Cakici, O.,Cheng, M.,Cheng, Q.Q.,Dementiev, A.,Eick, M.,Ferdyan, N.,Fontano, E.,Forman, A.,Kozlowski, R.,Lee, S.W.,Mehta, S.,Mowery, K.,Murray, B.,Nguyen, V.,Olland, A.,Phan, K.B.,Rivera, L.,Sabat, M.,Sprengeler, P.,Srinivasan, K.,Sun, Z.,Suto, R.K.,Wilkinson, T.,Wang, C.,Yu, N.,Xu, M.,Goel, V.,Hirst, G.,Reich, S.
Identification of a p21-activated kinase 1 (PAK1) inhibitor with 10-fold selectivity against PAK2.
Bioorg.Med.Chem.Lett., 127:130307-130307, 2025

PubMed 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.

PubMed: 40516764
DOI: 10.1016/j.bmcl.2025.130307

Experimental method

X-RAY DIFFRACTION (1.847 Å)