ArticleChemMedChem2012
Structural characterization and computer-aided optimization of a small-molecule inhibitor of the Arp2/3 complex, a key regulator of the actin cytoskeleton.
Article in ChemMedChem, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
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Who cites it
19 citing papers in PubMed, 39 citations in OpenAlex.
- Please inhibit responsibly: Natural and synthetic actin toxins as useful tools in cell biology.Molecular biology of the cell · 2025Review
- Article
- CK-666 and CK-869 differentially inhibit Arp2/3 iso-complexes.EMBO reports · 2024Article
- Herpes Simplex Virus Type 1 Infection Induces the Formation of Tunneling Nanotubes.Microorganisms · 2023Article
- Increased cross-presentation by dendritic cells and enhanced anti-tumour therapy using the Arp2/3 inhibitor CK666.British journal of cancer · 2023Article
- The Impact of Arp2/3 Complex Inhibition on Cytoskeleton Dynamics and Mitochondrial Function during Goat Oocyte Meiosis.Animals : an open access journal from MDPI · 2023Article
- Alterations to the broad-spectrum formin inhibitor SMIFH2 modulate potency but not specificity.Scientific reports · 2022Article
- Synthesis, Screening and Characterization of Novel Potent Arp2/3 Inhibitory Compounds Analogous to CK-666.Frontiers in pharmacology · 2022Article
- Actin-related protein 2/3 complex plays a critical role in the aquaporin-2 exocytotic pathway.American journal of physiology. Renal physiology · 2021Article
- Conserved actin machinery drives microtubule-independent motility and phagocytosis in Naegleria.The Journal of cell biology · 2020Article
- Potent, Selective, Water Soluble, Brain-Permeable EP2 Receptor Antagonist for Use in Central Nervous System Disease Models.Journal of medicinal chemistry · 2020Article
- Morphodynamics of the Actin-Rich Cytoskeleton inFrontiers in cellular and infection microbiology · 2018Article
- Using physics-based pose predictions and free energy perturbation calculations to predict binding poses and relative binding affinities for FXR ligands in the D3R Grand Challenge 2.Journal of computer-aided molecular design · 2018Article
- Membrane Protein Structure, Function, and Dynamics: a Perspective from Experiments and Theory.The Journal of membrane biology · 2015Review
- 1,2-Azaborine: The Boron-Nitrogen Derivative of ortho-Benzyne.Angewandte Chemie (International ed. in English) · 2015Article
- Structure-based virtual screening for drug discovery: principles, applications and recent advances.Current topics in medicinal chemistry · 2014Review
- Arp2/3 complex inhibitors adversely affect actin cytoskeleton remodeling in the cultured murine kidney collecting duct M-1 cells.Cell and tissue research · 2013Article
- Small molecules CK-666 and CK-869 inhibit actin-related protein 2/3 complex by blocking an activating conformational change.Chemistry & biology · 2013Article
- New insights into the regulation and cellular functions of the ARP2/3 complex.Nature reviews. Molecular cell biology · 2013Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.