9WDF

Crystal structure of PAK4-KPT-7523 complex

This is a non-PDB format compatible entry.

Summary for 9WDF

• Entry DOI: 10.2210/pdb9wdf/pdb
• Descriptor: Serine/threonine-protein kinase PAK 4, (~{E})-3-(6-azanylpyridin-3-yl)-~{N}-[[(2~{S})-7-chloranyl-5-(4-piperazin-1-ylcarbonylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]prop-2-enamide (3 entities in total)
• Functional Keywords: serine/threonine-protein kinase pak 4, transferase, structural protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 12
• Total formula weight: 408568.62

Authors

Lee, S.J.,Park, J. (deposition date: 2025-08-19, release date: 2026-07-29)

Primary citation

Park, J.,Hong, H.R.,Han, S.H.,Song, J.,Son, S.Y.,Choi, S.,Park, S.M.,Lee, W.K.,Jiko, C.,Kim, J.H.,Jee, J.G.,Bang, J.K.,Park, I.Y.,Lee, S.J.
Structural basis for a p21-activated kinase 4 and nicotinamide phosphoribosyltransferase dual inhibitor.
Acta Crystallogr D Struct Biol, 2026

PubMed Abstract: Simultaneous inhibition of oncogenic signaling and metabolic pathways represents a promising approach for cancer therapy. KPT-9274, a clinical stage compound, has been reported as a dual inhibitor of p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase (NAMPT), but its structural basis has remained undefined. Here, we present high-resolution crystal structures of PAK4 and NAMPT in complex with KPT-7523, an analog of KPT-9274, determined at 2.20 and 1.45 Å resolution, respectively. In PAK4, the 2-aminopyridine moiety of KPT-7523 enables dual binding, occupying the adenine-binding site for ATP and simultaneously engaging the substrate-binding cleft in the C-lobe, thereby interfering with both catalytic and regulatory functions. In NAMPT, the same scaffold inserts into the NAD active site in an extended conformation that preserves critical interactions. Biophysical assays revealed distinct affinities across the two targets. These findings highlight the 2-aminopyridine moiety as a versatile pharmacophore that is adaptable to structurally unrelated proteins and provide a framework for designing next-generation dual inhibitors in cancer therapy.

PubMed: 42473948
DOI: 10.1107/S2059798326006145

Experimental method

X-RAY DIFFRACTION (2.2 Å)