ML278 is a scavenger receptor-BI ( SR-BI ) inhibitor with an IC50 of 0.93 nM in mice. ML278 inhibits SR-BI -mediated lipid uptake, enhances the binding of high-density lipoprotein (HDL) to SR-BI, blocks the uptake of oleoylcholesteryl ester from HDL, and reversibly inhibits the efflux of free cholesterol to HDL particles. ML278 can be used in studies related to atherosclerotic coronary artery disease [1].
In Vitro, ML278 (dose range; 2 h) potently and reversibly inhibits DiI-HDL uptake in ldlA[mSR-BI] cells with an average IC50 of 6 nM[1]. ML278 (dose range) inhibits [3H]CE-HDL uptake in ldlA[mSR-BI] cells with an IC50 of 7 nM, which is more potent than ITX-5061[1]. ML278 (dose range) increases Alexa488-HDL binding to SR-BI in ldlA[mSR-BI] cells with an EC50 of 0.035 μM[1]. ML278 (Up to 35 μM; 3 h) potently inhibits murine SR-BI-mediated DiI-HDL uptake in ldlA[mSR-BI] CHO cells with an IC50 of 0.93 nM, and shows no SR-BI-independent activity in ldlA7 CHO cells at concentrations up to 35 μM[2]. ML278 (Up to 35 μM) increases human HDL binding to murine SR-BI in ldlA[mSR-BI] CHO cells with an AC50 of 0.035 μM[2]. ML278 (1 h pretreatment, then 2 h incubation) reduces SR-BI-mediated free cholesterol efflux to HDL in both wild-type and SR-BIC384S mutant SR-BI-expressing ldlA CHO cells, indicating it acts independently of the BLT-1 binding site at cysteine 384[2]. ML278 (3 h pre-treatment, followed by 3 h DiI-HDL incubation without ML278; 3 h pre-treatment, 4 h washout, followed by 3 h DiI-HDL incubation without ML278) acts as a reversible inhibitor of SR-BI-mediated DiI-HDL uptake in ldlA[mSR-BI] CHO cells, as its inhibitory activity is lost or reduced after compound washout[2]. ML278 (0.1-1 μM; 60 min preincubation, followed by 4 h incubation with [3H]CE-HDL) directly interacts with purified murine SR-BI to inhibit selective [3H]CE-HDL uptake into SR-BI-reconstituted liposomes, confirming its direct target activity[2]. ML278 (5 h) exhibits excellent stability in human plasma, with >99% remaining after 5 h, and is 94% plasma protein-bound[1]. ML278 (1 h) has moderate metabolic stability, with 75% remaining after 1 h in CD-1 mouse liver microsomes and 48% remaining in human liver microsomes[1]. ML278 (24 h) is noncytotoxic to ldlA[mSR-BI] cells after 24 h incubation[1]. ML278 (10 μM) inhibits 11 off-target receptors by ≥20%, with the greatest inhibition (43%) against the Adenosine A3 receptor[1]. ML278 has a measurable aqueous solubility of 0.57 μM in PBS[1]. ML278 (Up to 35 μM; 3 h, 24 h) shows no cytotoxicity in ldlA[mSR-BI] CHO cells after 3-hour or 24-hour incubation, with a cytotoxicity IC50 >35 μM[2]. ML278 (35 μM; 3 h pre-treatment, followed by 30 min transferrin incubation) does not inhibit clathrin-mediated transferrin endocytosis in ldlA[mSR-BI] CHO cells at concentrations up to 35 μM, demonstrating selective activity against SR-BI[2]. ML278 (48 h (PBS stability), 5 h (human plasma stability)) has a solubility of 0.57 µM in PBS with 1% DMSO, is stable in PBS over 48 hours and in human plasma over 5 hours, and is 93.5% bound to human plasma proteins[2].
References:
[1]. Dockendorff C, et al. Indolinyl-Thiazole Based Inhibitors of Scavenger Receptor-BI (SR-BI)-Mediated Lipid Transport. ACS Med Chem Lett. 2015 Feb 2;6(4):375-380.
[2]. Faloon PW, et al. A Small Molecule Inhibitor of Scavenger Receptor BI-mediated Lipid Uptake—Probe 1. 2011 Dec 15 [updated 2014 Sep 18]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010–.
In Vitro, ML278 (dose range; 2 h) potently and reversibly inhibits DiI-HDL uptake in ldlA[mSR-BI] cells with an average IC50 of 6 nM[1]. ML278 (dose range) inhibits [3H]CE-HDL uptake in ldlA[mSR-BI] cells with an IC50 of 7 nM, which is more potent than ITX-5061[1]. ML278 (dose range) increases Alexa488-HDL binding to SR-BI in ldlA[mSR-BI] cells with an EC50 of 0.035 μM[1]. ML278 (Up to 35 μM; 3 h) potently inhibits murine SR-BI-mediated DiI-HDL uptake in ldlA[mSR-BI] CHO cells with an IC50 of 0.93 nM, and shows no SR-BI-independent activity in ldlA7 CHO cells at concentrations up to 35 μM[2]. ML278 (Up to 35 μM) increases human HDL binding to murine SR-BI in ldlA[mSR-BI] CHO cells with an AC50 of 0.035 μM[2]. ML278 (1 h pretreatment, then 2 h incubation) reduces SR-BI-mediated free cholesterol efflux to HDL in both wild-type and SR-BIC384S mutant SR-BI-expressing ldlA CHO cells, indicating it acts independently of the BLT-1 binding site at cysteine 384[2]. ML278 (3 h pre-treatment, followed by 3 h DiI-HDL incubation without ML278; 3 h pre-treatment, 4 h washout, followed by 3 h DiI-HDL incubation without ML278) acts as a reversible inhibitor of SR-BI-mediated DiI-HDL uptake in ldlA[mSR-BI] CHO cells, as its inhibitory activity is lost or reduced after compound washout[2]. ML278 (0.1-1 μM; 60 min preincubation, followed by 4 h incubation with [3H]CE-HDL) directly interacts with purified murine SR-BI to inhibit selective [3H]CE-HDL uptake into SR-BI-reconstituted liposomes, confirming its direct target activity[2]. ML278 (5 h) exhibits excellent stability in human plasma, with >99% remaining after 5 h, and is 94% plasma protein-bound[1]. ML278 (1 h) has moderate metabolic stability, with 75% remaining after 1 h in CD-1 mouse liver microsomes and 48% remaining in human liver microsomes[1]. ML278 (24 h) is noncytotoxic to ldlA[mSR-BI] cells after 24 h incubation[1]. ML278 (10 μM) inhibits 11 off-target receptors by ≥20%, with the greatest inhibition (43%) against the Adenosine A3 receptor[1]. ML278 has a measurable aqueous solubility of 0.57 μM in PBS[1]. ML278 (Up to 35 μM; 3 h, 24 h) shows no cytotoxicity in ldlA[mSR-BI] CHO cells after 3-hour or 24-hour incubation, with a cytotoxicity IC50 >35 μM[2]. ML278 (35 μM; 3 h pre-treatment, followed by 30 min transferrin incubation) does not inhibit clathrin-mediated transferrin endocytosis in ldlA[mSR-BI] CHO cells at concentrations up to 35 μM, demonstrating selective activity against SR-BI[2]. ML278 (48 h (PBS stability), 5 h (human plasma stability)) has a solubility of 0.57 µM in PBS with 1% DMSO, is stable in PBS over 48 hours and in human plasma over 5 hours, and is 93.5% bound to human plasma proteins[2].
References:
[1]. Dockendorff C, et al. Indolinyl-Thiazole Based Inhibitors of Scavenger Receptor-BI (SR-BI)-Mediated Lipid Transport. ACS Med Chem Lett. 2015 Feb 2;6(4):375-380.
[2]. Faloon PW, et al. A Small Molecule Inhibitor of Scavenger Receptor BI-mediated Lipid Uptake—Probe 1. 2011 Dec 15 [updated 2014 Sep 18]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010–.