Document Detail


Discovery of MINC1, a GTPase-Activating Protein Small Molecule Inhibitor, Targeting MgcRacGAP.
MedLine Citation:
PMID:  25479424     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
The Rho family of Ras superfamily small GTPases regulates a broad range of biological processes such as migration, differentiation, cell growth and cell survival. Therefore, the availability of small molecule modulators as tool compounds could greatly enhance research on these proteins and their biological function. To this end, we designed a biochemical, high throughput screening assay with complementary follow-up assays to identify small molecule compounds inhibiting MgcRacGAP, a Rho family GTPase activating protein involved in cytokinesis and transcriptionally upregulated in many cancers. We first performed an in-house screen of 20,480 compounds, and later we tested the assay against 342,046 compounds from the NIH Molecular Libraries Small Molecule Repository. Primary screening hit rates were about 1% with the majority of those affecting the primary readout, an enzymecoupled GDP detection assay. After orthogonal and counter screens, we identified two hits with high selectivity towards MgcRacGAP, compared with other RhoGAPs, and potencies in the low micromolar range. The most promising hit, termed MINC1, was then examined with cell-based testing where it was observed to induce an increased rate of cytokinetic failure and multinucleation in addition to other cell division defects, suggesting that it may act as an MgcRacGAP inhibitor also in cells.
Authors:
Arjan J van Adrichem; Annika Fagerholm; Laura Turunen; Anna Lehto; Jani Saarela; Ari Koskinen; Gretchen A Repasky; Krister Wennerberg
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-12-04
Journal Detail:
Title:  Combinatorial chemistry & high throughput screening     Volume:  -     ISSN:  1875-5402     ISO Abbreviation:  Comb. Chem. High Throughput Screen.     Publication Date:  2014 Dec 
Date Detail:
Created Date:  2014-12-5     Completed Date:  -     Revised Date:  2014-12-6    
Medline Journal Info:
Nlm Unique ID:  9810948     Medline TA:  Comb Chem High Throughput Screen     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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