9WDF

Crystal structure of PAK4-KPT-7523 complex

これはPDB形式変換不可エントリーです。

9WDF の概要

• エントリーDOI: 10.2210/pdb9wdf/pdb
• 分子名称: 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)
• 機能のキーワード: serine/threonine-protein kinase pak 4, transferase, structural protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 408568.62

構造登録者

Lee, S.J.,Park, J. (登録日: 2025-08-19, 公開日: 2026-07-29)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.2 Å)