title: Indolinyl-Thiazole Based Inhibitors of Scavenger Receptor-BI (SR-BI)-Mediated Lipid Transport.
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.
authors.affiliation: 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.
authors.forename: Chris
authors.initials: C
authors.lastname: Dockendorff
authors.affiliation: Center for the Science of Therapeutics, Broad Institute , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Patrick W
authors.initials: PW
authors.lastname: Faloon
authors.affiliation: Department of Biology, Massachusetts Institute of Technology , 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Miao
authors.initials: M
authors.lastname: Yu
authors.affiliation: Center for the Science of Therapeutics, Broad Institute , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Willmen
authors.initials: W
authors.lastname: Youngsaye
authors.affiliation: Department of Biology, Massachusetts Institute of Technology , 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Marsha
authors.initials: M
authors.lastname: Penman
authors.affiliation: 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.
authors.forename: Thomas J F
authors.initials: TJ
authors.lastname: Nieland
authors.affiliation: Center for the Science of Therapeutics, Broad Institute , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Partha P
authors.initials: PP
authors.lastname: Nag
authors.affiliation: Center for the Science of Therapeutics, Broad Institute , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Lewis
authors.affiliation: Center for the Science of Therapeutics, Broad Institute , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Pu
authors.affiliation: Center for the Science of Therapeutics, Broad Institute , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Melissa
authors.initials: M
authors.lastname: Bennion
authors.affiliation: Center for the Science of Therapeutics, Broad Institute , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Negri
authors.affiliation: Center for the Science of Therapeutics, Broad Institute , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Conor
authors.initials: C
authors.lastname: Paterson
authors.affiliation: Center for the Science of Therapeutics, Broad Institute , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Garrett
authors.initials: G
authors.lastname: Lam
authors.affiliation: Center for the Science of Therapeutics, Broad Institute , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Sivaraman
authors.initials: S
authors.lastname: Dandapani
authors.affiliation: Center for the Science of Therapeutics, Broad Institute , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: José R
authors.initials: JR
authors.lastname: Perez
authors.affiliation: Center for the Science of Therapeutics, Broad Institute , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Benito
authors.initials: B
authors.lastname: Munoz
authors.affiliation: Center for the Science of Therapeutics, Broad Institute , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Palmer
authors.affiliation: 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.
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
authors.affiliation: Department of Biology, Massachusetts Institute of Technology , 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Monty
authors.initials: M
authors.lastname: Krieger
keywords: HCV; HDL receptor; HTS; ML278; MLP; SR-BI inhibitor; indoline; reverse cholesterol transport; thiazole