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Updated: Aug 6, 2026

Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
13:22

Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays

Published on: October 23, 2019

Structural basis for a p21-activated kinase 4 and nicotinamide phosphoribosyltransferase dual inhibitor

Jaehui Park1, Hye Rim Hong2, Sang Hyun Han1

  • 1College of Pharmacy, Chungbuk National University, Chungbuk 28160, South Korea.

Acta Crystallographica. Section D, Structural Biology
|July 20, 2026
PubMed

Insights

This study reveals the structural basis for KPT-7523, a dual inhibitor of p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase (NAMPT), offering insights for novel cancer therapies.

Area of Science:

  • Structural biology
  • Molecular pharmacology
  • Cancer therapeutics

Background:

  • Simultaneous inhibition of oncogenic signaling and metabolic pathways is a key strategy in cancer therapy.
  • KPT-9274 is a dual inhibitor of p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase (NAMPT), but its structural mechanism is unknown.

Purpose of the Study:

  • To elucidate the structural basis of dual inhibition by KPT-9274, an analog, on PAK4 and NAMPT.
  • To provide a structural framework for developing next-generation dual inhibitors for cancer treatment.

Main Methods:

  • High-resolution crystal structures of PAK4 and NAMPT complexed with KPT-7523 were determined.
  • Structural analysis focused on the binding modes and interactions of KPT-7523 within the active sites.
  • Biophysical assays were employed to assess target affinities.

Main Results:

  • Crystal structures revealed KPT-7523 binding to PAK4 and NAMPT at 2.20 Å and 1.45 Å resolution, respectively.
  • In PAK4, KPT-7523's 2-aminopyridine moiety binds dual sites, inhibiting catalytic and regulatory functions.
  • In NAMPT, KPT-7523 binds the NAD+ active site, preserving key interactions; distinct affinities were observed for each target.

Conclusions:

  • The 2-aminopyridine moiety acts as a versatile pharmacophore adaptable to different protein targets.
  • These structural insights facilitate the design of advanced dual inhibitors for enhanced cancer therapy.
  • The study provides a foundation for developing novel therapeutic strategies targeting both signaling and metabolic pathways in cancer.
Keywords:
2-aminopyridine pharmacophoreKPT-7523NAMPTPAK4dual inhibition

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