ML151

ML151

Target Name

Thyroid Hormone Receptor Beta

Target Alias

THRB

Target Class

C4 Zinc Finger Nuclear Receptor

Mechanism of Action

Inhibitor of THRB

Biological / Disease Relevance

TR-SRC2 interactions, Nuclear Hormone Receptorcoactivator Interactions

In vitro activity

TR-SRC2 bioassay (IC50)

1.40 uM

In vitro activity

TR-SRC2 alpha screen

2.7 uM

Target Information

Thyroid hormone receptors (TRs) are members of the nuclear hormone receptor superfamily and regulate many homeostatic processes, including basal metabolism, cardiovascular function, body weight, and lipid trafficking. Upon binding of the ligand triiodothyronine (T3), TR undergoes a conformational change that releases corepressors and recruits coactivators, such as Steroid Receptor Coactivator 2 (SRC2); in turn, these modulate the expression of target genes. This inhibitor probe molecule, ML151 (CID 5184800), blocked TRβ-SRC2 interaction with a potency of 1.8μM. Mechanistic studies revealed that ML151 is a covalent inhibitor and binds irreversibly to Cys298 within the AF-2 cleft of TRβ. This series will be useful for in vitro mechanistic studies of TR-SRC2 interactions, as well as other nuclear hormone receptorcoactivator interactions.

Properties

NCGC00188612

Physical & chemical properties
Molecular Weight	436.5 g/mol
Molecular Formula	C20H24N2O7S
cLogP	2.9
PSA	144
Storage
Solubility	10mM in DMSO; 2.9 uM in PBS buffer
CAS Number	573965-48-7

SMILES:
CS(=O)(C1=C([N+]([O-])=O)C=C(C(OCC(NC23CC4CC(C3)CC(C2)C4)=O)=O)C=C1)=O

InChI:
InChI=1S/C20H24N2O7S/c1-30(27,28)17-3-2-15(7-16(17)22(25)26)19(24)29-11-18(23)21-20-8-12-4-13(9-20)6-14(5-12)10-20/h2-3,7,12-14H,4-6,8-11H2,1H3,(H,21,23)

InChIKey:
BTXTVUJWNPMQBT-UHFFFAOYSA-N

Activity

Summary activity statement /

ML151 (SID 87550784; SID 87550851; CID 5184800) is a small molecule inhibitors of SRC2 interaction with TR. ML151 is observed to be an irreversible inhibitor with a potency in the low micro molar (IC50). Unlike previously known TR-SRC2 (protein-protein binding) inhibitors, this probe has less off-target liability and doesn’t seem to block other Hormone Receptor activity.

In vitro activity - Selectivity Assay

Bioassays	ML151 (IC50)
TR-SRC2	1.4 uM
AR-SRC2	> 130 uM
VDR-SRC2	53 uM
PPARg-DRIP	> 130 uM

Summary /

ML151 is observed to be > 92, 38, and > 92 fold selective against TR-SRC2 interaction vs. Androgen Receptor (AR) -SRC2, Vitamin D Receptor (VDR) – SRC2, and Peroxisome Proliferator-Activated Receptor Gamma (PPARg) assays respectively.

In vitro activity - Cellular Activity

Summary /

HEK293 cells were co-transfected with a CMV-TRβ expression vector, a Photonis luciferase reporter fused to a thyroid response element and a Renilla luciferase reporter, used as a control for transfection efficiency. Cells were treated with 30 nM T3 and different concentrations of ML151 (compound 1), incubated for 18 hours, and transcriptional reporter activities measured. ML151 showed a concentration-dependent decrease of TRβ-mediated activity over the tested concentration range of 2.5 to 20 μM (Hwang 2011).

Figure 1. Percent inhibition of T3-induced TRE-luciferase activity in HEK293 cells. A) T3-mediated transcription is reduced by MSNB analogs (1 = ML151 probe). HEK293 cells were transfected with CMV-TRbeta- and DR4-TRE-driven luciferase expression vectors. The data were normalized to Renilla luciferase activity. B) cell viability based on Renilla luciferase activity. Error bars represent S.D. of two independent experiments performed in triplicate. **, p < 0.01; ***, p < 0.005.

ML151 : THRB (Thyroid Hormone Receptor Beta) Inhibitor

In vitro activity

In vitro activity

Target Information

Properties

ML151

NCGC00188612

Activity

In vitro activity - Selectivity Assay

In vitro activity - Cellular Activity

References