Home Endocrinology & Hormones Estrogen/progestogen Receptor antagonist Brilanestrant (GDC-0810)

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Brilanestrant (GDC-0810) Estrogen/progestogen Receptor antagonist

Cat.No.S7855

Brilanestrant (GDC-0810, ARN-810) is a potent ER-α binder (ER-α, IC50 = 6.1 nM; ER-β, IC50 = 8.8 nM). This compound is a full transcriptional antagonist with no agonism and displays good potency and efficacy in ER-α degradation (EC50 = 0.7 nM) and MCF-7 breast cancer cell viability (IC50 = 2.5 nM) assays with good selectivity over other nuclear hormone receptors.
Brilanestrant (GDC-0810) Estrogen/progestogen Receptor antagonist Chemical Structure

Chemical Structure

Molecular Weight: 446.90

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Quality Control

Batch: S785501 DMSO]89 mg/mL]false]Ethanol]89 mg/mL]false]Water]Insoluble]false Purity: 99.98%
99.98

Solubility

In vitro
Batch:

DMSO : 89 mg/mL (199.14 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Ethanol : 89 mg/mL

Water : Insoluble

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In vivo
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Chemical Information, Storage & Stability

Molecular Weight 446.90 Formula

C26H20ClFN2O2

 Storage (From the date of receipt)
CAS No. 1365888-06-7 -- Storage of Stock Solutions

Synonyms ARN-810 Smiles CCC(=C(C1=CC=C(C=C1)C=CC(=O)O)C2=CC3=C(C=C2)NN=C3)C4=C(C=C(C=C4)F)Cl

Mechanism of Action

Targets/IC50/Ki
ERα
(Cell-free)
6.1 nM
ERβ
(Cell-free)
8.8 nM
In vitro
In cell-free radio-ligand competitive binding assays, Brilanestrant (GDC-0810) binds both ERα and ERβ with low nanomolar affinity. This compound has little to no inhibition against CYP1A2, CYP2D6, or CYP3A4 (IC50 > 20 μM), modest inhibitory effect on CYP2C9 and CYP2C19 (IC50 = 2.2 and 3.3 μM respectively), and potent inhibition of CYP2C8 (IC50 of <0.1 μM). Selectivity of it over other nuclear hormone receptors is also found to be good. In transcriptional reporter assays for the mineralocorticoid (MR), progesterone-A (PR-A), progesterone (PR-B), and glucocorticoid (GR) receptors, it has minimal activity (IC50 > 1 μM). While in binding assays, it displays little activity toward the androgen receptor (AR; IC50 > 4 μM) and GR (IC50 = 0.99 μM). GDC-0810-mediated ERα depletion is dependent on the 26S proteasome. It antagonizes ERα ligand binding domain mutants in vitro and in vivo. In cell-free E2 competitive binding assays that was used to determine the binding of this compound to ER.WT, ER.Y537S and ER.D538G ligand binding domains, it retains its ability to potently displace E2 from the ligand binding domain, albeit with a slightly increased IC50 (WT: 2.6 nM vs. ER.Y537S: 5.5 nM and ER.D538G: 5.4 nM). It can compete the PGC1α co-activator peptide off the mutated ligand binding domain, implying that it is capable of driving an 'active' to 'inactive' conformational shift of mutant ER, though with a ~five-seven fold reduction in biochemical potency compared to wild-type ER.
In vivo
Brilanestrant (GDC-0810) exhibits a pharmacokinetic profile characterized by low clearance across species and good bioavailability (40–60%). As would be expected for a lipophilic carboxylic acid, the compound is highly bound to plasma proteins (>99.5% across species) and has a low to moderate volume of distribution (Vss = 0.2–2.0 L/kg across species). It demonstrates good bioavailability across species and displays robust activity in tamoxifen-sensitive and tamoxifen-resistant xenograft models of breast cancer. This compound also exhibits mild estrogenic activity in uterine models in vitro and in vivo.
References

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT02802670 Completed
Healthy Volunteers
Genentech Inc.
 May 2016 Phase 1
NCT02621957 Completed
Breast Cancer
Genentech Inc.
 December 2015 Phase 1
NCT02569801 Terminated
Breast Cancer
Genentech Inc.
 December 4 2015 Phase 2
NCT01823835 Terminated
Breast Cancer
Genentech Inc.
 December 29 2014 Phase 1|Phase 2

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