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.
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Authors | Andrew W Baggett, Zoe Cournia, Min Suk Han, George Patargias, Adam C Glass, Shih-Yuan Liu, Brad J Nolen |
Journal | ChemMedChem
(ChemMedChem)
Vol. 7
Issue 7
Pg. 1286-94
(Jul 2012)
ISSN: 1860-7187 [Electronic] Germany |
PMID | 22623398
(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.)
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Copyright | Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. |
Chemical References |
- Actin-Related Protein 2-3 Complex
- Small Molecule Libraries
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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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