2. Academic Validation
  3. Indolinyl-Thiazole Based Inhibitors of Scavenger Receptor-BI (SR-BI)-Mediated Lipid Transport

Indolinyl-Thiazole Based Inhibitors of Scavenger Receptor-BI (SR-BI)-Mediated Lipid Transport

  • ACS Med Chem Lett. 2015 Feb 2;6(4):375-380. doi: 10.1021/ml500154q.
Chris Dockendorff 1,  Patrick W Faloon 2,  Miao Yu 3,  Willmen Youngsaye 2,  Marsha Penman 3,  Thomas J F Nieland 4,  Partha P Nag 2,  Timothy A Lewis 2,  Jun Pu 2,  Melissa Bennion 2,  Joseph Negri 2,  Conor Paterson 2,  Garrett Lam 2,  Sivaraman Dandapani 2,  José R Perez 2,  Benito Munoz 2,  Michelle A Palmer 2,  Stuart L Schreiber 5,  Monty Krieger 3
Affiliations

Affiliations

  • 1 Center for the Science of Therapeutics, Broad Institute , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States ; Department of Chemistry, Marquette University , Milwaukee, Wisconsin 53201-1881, United States.
  • 2 Center for the Science of Therapeutics, Broad Institute , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
  • 3 Department of Biology, Massachusetts Institute of Technology , 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
  • 4 Department of Biology, Massachusetts Institute of Technology , 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States ; Center for the Science of Therapeutics, Broad Institute , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
  • 5 Center for the Science of Therapeutics, Broad Institute , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States ; Howard Hughes Medical Institute, Broad Institute , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
PMID: 26478787 DOI: 10.1021/ml500154q
Abstract

A potent class of indolinyl-thiazole based inhibitors of cellular lipid uptake mediated by scavenger receptor, class B, type I (SR-BI) was identified via a high-throughput screen of the National Institutes of Health Molecular Libraries Small Molecule Repository (NIH MLSMR) in an assay measuring the uptake of the fluorescent lipid DiI from HDL particles. This class of compounds is represented by ML278 (17-11), a potent (average IC50 = 6 nM) and reversible inhibitor of lipid uptake via SR-BI. ML278 is a plasma-stable, noncytotoxic probe that exhibits moderate metabolic stability, thus displaying improved properties for in vitro and in vivo studies. Strikingly, ML278 and previously described inhibitors of lipid transport share the property of increasing the binding of HDL to SR-BI, rather than blocking it, suggesting there may be similarities in their mechanisms of action.

Keywords

HCV; HDL receptor; HTS; ML278; MLP; SR-BI inhibitor; indoline; reverse cholesterol transport; thiazole.

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