A small-molecule screening strategy to identify suppressors of statin myopathy.

ACS Chem Biol
Authors
Keywords
Abstract

The reduction of plasma low-density lipoprotein levels by HMG-CoA reductase inhibitors, or statins, has had a revolutionary impact in medicine, but muscle-related side effects remain a dose-limiting toxicity in many patients. We describe a chemical epistasis approach that can be useful in refining the mechanism of statin muscle toxicity, as well as in screening for agents that suppress muscle toxicity while preserving the ability of statins to increase the expression of the low-density lipoprotein receptor. Using this approach, we identified one compound that attenuates the muscle side effects in both cellular and animal models of statin toxicity, likely by influencing Rab prenylation. Our proof-of-concept screen lays the foundation for truly high-throughput screens that could help lead to the development of clinically useful adjuvants that can one day be co-administered with statins.

Year of Publication
2011
Journal
ACS Chem Biol
Volume
6
Issue
9
Pages
900-4
Date Published
2011 Sep 16
ISSN
1554-8937
DOI
10.1021/cb200206w
PubMed ID
21732624
PubMed Central ID
PMC3176973
Links
Grant list
DP2 DK-083048 / DK / NIDDK NIH HHS / United States
R24 DK-080261 / DK / NIDDK NIH HHS / United States
DP2 DK083048 / DK / NIDDK NIH HHS / United States
R24 DK080261 / DK / NIDDK NIH HHS / United States
R24 DK080261-05 / DK / NIDDK NIH HHS / United States
Howard Hughes Medical Institute / United States