4ZY4: Crystal Structure Of P21 Activated Kinase 1 In Complex With An Inhibitor Compound 4

The p21-activated kinases (PAKs) play important roles in cytoskeletal organization, cellular morphogenesis, and survival and have generated significant attention as potential therapeutic targets for cancer. Following a high-throughput screen, we identified an aminopyrazole scaffold-based series that was optimized to yield group I selective PAK inhibitors. A structure-based design effort aimed at targeting the ribose pocket for both potency and selectivity led to much-improved group I vs II selectivity. Early lead compounds contained a basic primary amine, which was found to be a major metabolic soft spot with in vivo clearance proceeding predominantly via N-acetylation. We succeeded in identifying replacements with improved metabolic stability, leading to compounds with lower in vivo rodent clearance and excellent group I PAK selectivity.
PDB ID: 4ZY4Download
MMDB ID: 130600
PDB Deposition Date: 2015/5/21
Updated in MMDB: 2015/07
Experimental Method:
x-ray diffraction
Resolution: 2.6  Å
Source Organism:
Similar Structures:
Biological Unit for 4ZY4: monomeric; determined by author
Molecular Components in 4ZY4
Label Count Molecule
Protein (1 molecule)
Serine/threonine-protein Kinase PAK 1(Gene symbol: PAK1)
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB