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Structural characterization and computer-aided optimization of a small-molecule inhibitor of the Arp2/3 complex, a key regulator of the actin cytoskeleton.

Abstract
CK-666 (1) is a recently discovered small-molecule inhibitor of the actin-related protein 2/3 (Arp2/3) complex, a key actin cytoskeleton regulator with roles in bacterial pathogenesis and cancer cell motility. Although 1 is commercially available, the crystal structure of Arp2/3 complex with 1 bound has not been reported, making its mechanism of action uncertain. Furthermore, its relatively low potency increases its potential for off-target effects in vivo, complicating interpretation of its influence in cell biological studies and precluding its clinical use. Herein we report the crystal structure of 1 bound to Arp2/3 complex, which reveals that 1 binds between the Arp2 and Arp3 subunits to stabilize the inactive conformation of the complex. Based on the crystal structure, we used computational docking and free-energy perturbation calculations of monosubstituted derivatives of 1 to guide optimization efforts. Biochemical assays of ten newly synthesized compounds led to the identification of compound 2, which exhibits a threefold increase in inhibitory activity in vitro relative to 1. In addition, our computational analyses unveiled a surface groove at the interface of the Arp2 and Arp3 subunits that can be exploited for additional structure-based optimization.
AuthorsAndrew W Baggett, Zoe Cournia, Min Suk Han, George Patargias, Adam C Glass, Shih-Yuan Liu, Brad J Nolen
JournalChemMedChem (ChemMedChem) Vol. 7 Issue 7 Pg. 1286-94 (Jul 2012) ISSN: 1860-7187 [Electronic] Germany
PMID22623398 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
CopyrightCopyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Chemical References
  • Actin-Related Protein 2-3 Complex
  • Small Molecule Libraries
Topics
  • Actin Cytoskeleton (drug effects, metabolism)
  • Actin-Related Protein 2-3 Complex (antagonists & inhibitors, metabolism)
  • Animals
  • Cattle
  • Computer-Aided Design
  • Dose-Response Relationship, Drug
  • Models, Molecular
  • Molecular Structure
  • Small Molecule Libraries (chemical synthesis, chemistry, pharmacology)
  • Stereoisomerism
  • Structure-Activity Relationship

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