Brilanestrant
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MedKoo CAT#: 206041

CAS#: 1365888-06-7

Description: Brilanestrant, also known as GDC-0810, ARN-810 and RG6046, an orally bioavailable Selective Estrogen Receptor Degrader (SERD) that demonstrates robust activity in tamoxifen-resistant breast cancer xenografts. GDC-0810 functions by binding to the estrogen receptor, inducing a conformational change resulting in the degradation of the receptor. GDC-0810 or ARN-810 demonstrates robust activity in models of tamoxifen-sensitive and tamoxifen-resistant breast cancer, and is currently in clinical trials in women with locally advanced or metastatic estrogen receptor-positive breast cancer.

Chemical Structure

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Brilanestrant
CAS# 1365888-06-7
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 206041
Name: Brilanestrant
CAS#: 1365888-06-7
Chemical Formula: C26H20ClFN2O2
Exact Mass: 446.12
Molecular Weight: 446.906
Elemental Analysis: C, 69.88; H, 4.51; Cl, 7.93; F, 4.25; N, 6.27; O, 7.16

Price and Availability

Size Price Availability Quantity
10mg USD 150 Ready to ship
25mg USD 250 Ready to ship
50mg USD 450 Ready to ship
100mg USD 650 Ready to ship
200mg USD 950 Ready to ship
500mg USD 1650 Ready to ship
1g USD 2950 Ready to ship
2g USD 5250 Ready to ship
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Synonym: GDC0810; GDC 0810; GDC-0810; ARN810; ARN 810; ARN-810; RG6046; RG-6046; RG 6046; Brilanestrant

IUPAC/Chemical Name: (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid

InChi Key: BURHGPHDEVGCEZ-KJGLQBJMSA-N

InChi Code: InChI=1S/C26H20ClFN2O2/c1-2-21(22-10-9-20(28)14-23(22)27)26(18-8-11-24-19(13-18)15-29-30-24)17-6-3-16(4-7-17)5-12-25(31)32/h3-15H,2H2,1H3,(H,29,30)(H,31,32)/b12-5+,26-21+

SMILES Code: O=C(O)/C=C/C1=CC=C(C=C1)/C(C2=CC3=C(NN=C3)C=C2)=C(CC)\C4=CC=C(C=C4Cl)F

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

More Info:         

Biological target: Brilanestrant (GDC-0810, ARN-810) is a potent ER-α binder (ER-α, IC50 = 6.1 nM; ER-β, IC50 = 8.8 nM), 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.
In vitro activity: GDC-0810-mediated ERα depletion is dependent on the 26S proteasome. GDC-0810 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 GDC-0810 to ER.WT, ER.Y537S and ER.D538G ligand binding domains, GDC-0810 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). GDC-0810 can compete the PGC1α co-activator peptide off the mutated ligand binding domain, implying that GDC-0810 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. Reference: Elife. 2016 Jul 13;5:e15828. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/27410477/
In vivo activity: In mice, GDC-0810 exhibits low clearance (11 mL/min/kg) and 61% oral bioavailability. Importantly, GDC-0810 plasma concentrations increase proportionately with the applied dose and achieve an AUC0–24 of 94.1 μg*hr/ml when dosed by oral gavage at 100 mg/kg/day (Supplementary file 2A). To determine the ability of GDC-0810 to inhibit E2 stimulated tumor growth in vivo, the MCF7 tumor bearing nu/nu mice were orthotopically implanted with 0.36 mg/60 day release E2 pellets with GDC-0810, ranging from 1 to 100 mg/kg/day p.o. Fulvestrant was delivered by sub-cutaneous injection, with an initial loading dose of 50 mg/kg on days 1, 3 and 8, and subsequent dosing of 25 mg/kg twice per week to achieve exposures similar to those achieved in the clinic. In the MCF7 xenograft model, GDC-0810 displayed dose dependent efficacy (Figure 4A). The 100 mg/kg/day dose caused tumor regressions; an effect similar to withdrawal of estrogen pellets at the start of dosing. In contrast, fulvestrant, at a clinically relevant dose as well as at a considerably higher dose (200 mg/kg, 3 times per week), yielded only modest tumor growth inhibition (Figure 4A and Figure 4—figure supplement 1A). It is important to note that the restriction of the fulvestrant response to tumor growth inhibition, rather than stasis or tumor regression, was not a function of low exposure, as the plasma concentrations at the 200 mg/kg dose were on average 12–14 µg*hr/mL, approximately 30-fold above the clinical exposure of the fulvestrant 500 mg clinical regimen. Gene expression analysis of harvested MCF7 tumors demonstrated that GDC-0810 (at 100 mg/kg/day, evaluated on day 28) robustly modulated ER target genes, including PGR, c-MYC, AREG and MUC1 (Figure 4B,C; Figure 4—figure supplement 1B). Indeed, the gene expression changes induced by GDC-0810 are similar to, and in some cases even more pronounced than, those induced by withdrawal of the estrogen pellet at the beginning of the study, highlighting that GDC-0810 actively and efficiently attenuates ER signaling (Figure 4B,C; Figure 4—figure supplement 1B). Reference: Elife. 2016 Jul 13;5:e15828. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/27410477/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 89.0 199.15
Ethanol 89.0 199.15

Preparing Stock Solutions

The following data is based on the product molecular weight 446.91 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol:
In vitro protocol: 1. Lai A, Kahraman M, Govek S, Nagasawa J, Bonnefous C, Julien J, Douglas K, Sensintaffar J, Lu N, Lee KJ, Aparicio A, Kaufman J, Qian J, Shao G, Prudente R, Moon MJ, Joseph JD, Darimont B, Brigham D, Grillot K, Heyman R, Rix PJ, Hager JH, Smith ND. Identification of GDC-0810 (ARN-810), an Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) that Demonstrates Robust Activity in Tamoxifen-Resistant Breast Cancer Xenografts. J Med Chem. 2015 Jun 25;58(12):4888-904. doi: 10.1021/acs.jmedchem.5b00054. Epub 2015 May 22. PMID: 25879485. 2. Joseph JD, Darimont B, Zhou W, Arrazate A, Young A, Ingalla E, Walter K, Blake RA, Nonomiya J, Guan Z, Kategaya L, Govek SP, Lai AG, Kahraman M, Brigham D, Sensintaffar J, Lu N, Shao G, Qian J, Grillot K, Moon M, Prudente R, Bischoff E, Lee KJ, Bonnefous C, Douglas KL, Julien JD, Nagasawa JY, Aparicio A, Kaufman J, Haley B, Giltnane JM, Wertz IE, Lackner MR, Nannini MA, Sampath D, Schwarz L, Manning HC, Tantawy MN, Arteaga CL, Heyman RA, Rix PJ, Friedman L, Smith ND, Metcalfe C, Hager JH. The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer. Elife. 2016 Jul 13;5:e15828. doi: 10.7554/eLife.15828. Erratum in: Elife. 2019 Jan 07;8: PMID: 27410477; PMCID: PMC4961458.
In vivo protocol: 1. Lai A, Kahraman M, Govek S, Nagasawa J, Bonnefous C, Julien J, Douglas K, Sensintaffar J, Lu N, Lee KJ, Aparicio A, Kaufman J, Qian J, Shao G, Prudente R, Moon MJ, Joseph JD, Darimont B, Brigham D, Grillot K, Heyman R, Rix PJ, Hager JH, Smith ND. Identification of GDC-0810 (ARN-810), an Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) that Demonstrates Robust Activity in Tamoxifen-Resistant Breast Cancer Xenografts. J Med Chem. 2015 Jun 25;58(12):4888-904. doi: 10.1021/acs.jmedchem.5b00054. Epub 2015 May 22. PMID: 25879485. 2. Joseph JD, Darimont B, Zhou W, Arrazate A, Young A, Ingalla E, Walter K, Blake RA, Nonomiya J, Guan Z, Kategaya L, Govek SP, Lai AG, Kahraman M, Brigham D, Sensintaffar J, Lu N, Shao G, Qian J, Grillot K, Moon M, Prudente R, Bischoff E, Lee KJ, Bonnefous C, Douglas KL, Julien JD, Nagasawa JY, Aparicio A, Kaufman J, Haley B, Giltnane JM, Wertz IE, Lackner MR, Nannini MA, Sampath D, Schwarz L, Manning HC, Tantawy MN, Arteaga CL, Heyman RA, Rix PJ, Friedman L, Smith ND, Metcalfe C, Hager JH. The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer. Elife. 2016 Jul 13;5:e15828. doi: 10.7554/eLife.15828. Erratum in: Elife. 2019 Jan 07;8: PMID: 27410477; PMCID: PMC4961458.

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1: Shah N, Mohammad AS, Saralkar P, Sprowls SA, Vickers SD, John D, Tallman RM, Lucke-Wold BP, Jarrell KE, Pinti M, Nolan RL, Lockman PR. Investigational chemotherapy and novel pharmacokinetic mechanisms for the treatment of breast cancer brain metastases. Pharmacol Res. 2018 Jun;132:47-68. doi: 10.1016/j.phrs.2018.03.021. Epub 2018 Mar 28. PMID: 29604436; PMCID: PMC5997530.


2: Chinnasamy K, Saravanan M, Poomani K. Evaluation of binding and antagonism/downregulation of brilanestrant molecule in estrogen receptor-α via quantum mechanics/molecular mechanics, molecular dynamics and binding free energy calculations. J Biomol Struct Dyn. 2020 Jan;38(1):219-235. doi: 10.1080/07391102.2019.1574605. Epub 2019 Apr 30. PMID: 31038398.


3: Cheff DM, Cheng Q, Guo H, Travers J, Klumpp-Thomas C, Shen M, Arnér ESJ, Hall MD. Development of an assay pipeline for the discovery of novel small molecule inhibitors of human glutathione peroxidases GPX1 and GPX4. Redox Biol. 2023 Jul;63:102719. doi: 10.1016/j.redox.2023.102719. Epub 2023 May 16. PMID: 37244126; PMCID: PMC10220285.