ML209 : RORG (M. musculus Nuclear Receptor ROR-gamma) Inhibitor
ML209
Target Name
M. musculus Nuclear Receptor ROR-gamma
Target Alias
RORG
Target Class
C4 Zinc Finger Nuclear Receptor
Mechanism of Action
Inhibitor of RORG
Biological / Disease Relevance
Th17-related autoimmune diseases, Th17 cell differentiation
In vitro activity
RORgamma bioassay (IC50)Cellular activity
Th17 cell differentiation assay (IC50)Target Information
The retinoic acid-related orphan receptor RORγt is required and plays a pivotal role in the differentiation of thymocytes, lymphoid tissue inducer cells, and inflammatory T helper-expressing interleukin 17a (Th17) cells. The identification of small molecules modulating RORγt activity may provide a means to regulate Th17 mediated immune response. While small molecule antagonists of RORγt have been identified, these inhibitors are neither selective nor potent below micromolar concentrations. The diphenylpropanamide probe series (ML209 and analogs) presented here selectively inhibits RORγt-mediated activity at submicromolar concentrations in cell assays, including thymocytes. This probe will be a useful pharmacological tool to study cellular activities controlled by RORγt. Furthermore, this diphenylpropanamide series represents a lead scaffold to develop novel therapeutics for Th17-related autoimmune diseases.
Properties
ML209
NCGC00238427-03
| Physical & chemical properties | ||||
|---|---|---|---|---|
| Molecular Weight | 441.5 g/mol | |||
| Molecular Formula | C25H31NO6 | |||
| cLogP | 4.2 | |||
| PSA | 77.5 Ų | |||
| Storage | ||||
| Solubility | ||||
| CAS Number | 1334526-14-5 | |||
SMILES:
COC1=CC(OC)=C(C(CC(N2C[C@@H](C[C@@H](C2)C)C)=O)C3=CC4=C(OCO4)C=C3)C(O)=C1
InChI:
InChI=1S/C25H31NO6/c1-15-7-16(2)13-26(12-15)24(28)11-19(17-5-6-21-22(8-17)32-14-31-21)25-20(27)9-18(29-3)10-23(25)30-4/h5-6,8-10,15-16,19,27H,7,11-14H2,1-4H3/t15-,16+,19?
InChIKey:
YEKVAIMYYCZDLI-MCPYQZEQSA-N
Activity
Summary activity statement /
In this report, we present the identification of a series of diphenylpropanamides as novel and selective RORγt antagonists. ML209 (SID 99455330; CID 53385590) inhibited transcriptional activity of RORγt, but not ROR-alpha, in cells. In addition, it suppressed Th17 cell differentiation at submicromolar concentrations.
In vitro activity - Selectivity and Cytotoxicity Assay
| Bioassay | ML209 (IC50) |
|---|---|
|
RORγt |
460 nM |
|
ROR-alpha (Anti-Target) |
Inactive up to 96 uM |
|
VP16 (Anti-Target) |
Inactive up to 96 uM |
|
Cytotoxicity |
Not Toxic |
Summary /
ML209 is found to have > 200 fold selective against the ROR-gamma vs. ROR-alpha and a Virus-encoded protein (VP16, induces gene trancription and is unrelated to ROR family memeber). The compound probe also showed no cytotoxicity at concentrations up to 96 uM.
In vitro activity - Nuclear Receptor Profiling Assay
Summary /
Profiling of the probe in a panel of 21 nuclear receptors for antagonistic activity showed that the probe had weak activities against 4 receptors, which are ERRα (IC50 = 14 μM), LXRα (IC50 = 10 μM), TRα (IC50 = 4.5 μM) and TRβ (IC50 = 13 μM).
Table 1. Profiling results for ML209 in a panel of 21 nuclear receptors for antagonistic activity.
References
- Quantitative high throughput screen for inhibitors of ROR gamma transcriptional activity: Summary
- Huang W, Wang H, Johnson RL, et al. Identification of Potent and Selective RORγ Antagonists. 2010 Dec 15 [Updated 2013 Feb 25]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010
- Huh JR, Englund EE, Wang H, et al. Identification of Potent and Selective Diphenylpropanamide RORγ Inhibitors. ACS Med Chem Lett. 2013;4(1):79-84. doi:10.1021/ml300286h