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Purity: ≥98%
GDC-0927 (formerly known as SRN-927) is a novel, potent, non-steroidal, orally bioavailable, selective ER (estrogen receptor) antagonist/ER degrader (SERD) that causes tumor regression in xenograft models grown from ER+ BC patients. As of right now, GDC-0927 looks to be well-tolerated. PK exposure appears to support QD dosing, there is evidence of strong PD target engagement, and heavily pretreated patients with advanced or metastatic ER+ BC—including those with ESR1 mutations—show encouraging anti-tumor activity. The potential for GDC-0927, an oral active SERD of the next generation, to surpass GDC-0810 as the best-in-class SERD molecule is apparent. GDC-0927 specifically targets the estrogen receptor alpha (ERα), a receptor that is expressed in over 70% of breast cancer cases, making it a commonly targeted target for the illness.
| Targets |
Estrogen receptor
Estrogen Receptor α (ERα) (Ki = 0.1 nM for human ERα; IC₅₀ = 0.3 nM for ERα binding inhibition; IC₅₀ = 0.7 nM for ERα degradation in MCF-7 cells) [1] |
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| ln Vitro |
GDC-0927 (formerly known as SRN-927) is a novel, potent, non-steroidal, orally bioavailable, selective ER (estrogen receptor) antagonist/ER degrader (SERD) that causes tumor regression in ER+ BC patient-derived xenograft models. With PK exposure supporting QD dosing, evidence of strong PD target engagement, and encouraging anti-tumor activity in heavily pretreated patients with advanced or metastatic ER+ BC, including patients with ESR1 mutations, GDC-0927 appears to be well tolerated so far. A next-generation orally active SERD called GDC-0927 appears to have more potential than GDC-0810 to be the best SERD molecule in its class. GDC-0927 targets the estrogen receptor alpha (ERα), which is a popular target for the disease because it is expressed in more than 70% of breast cancers.
ERα binding and degradation: GDC-0927 is a potent oral selective estrogen receptor degrader (SERD) that binds to human ERα with high affinity (Ki = 0.1 nM) and inhibits ERα binding to estrogen response elements (ERE) with an IC₅₀ of 0.3 nM. It dose-dependently induces ERα degradation in ER+ breast cancer cell lines, achieving 90% ERα degradation at 1 nM in MCF-7 cells (IC₅₀ = 0.7 nM) and 85% degradation at 1 nM in T47D cells (IC₅₀ = 0.9 nM) [1] - Antiproliferative activity: GDC-0927 inhibits proliferation of ER+ HER2- breast cancer cell lines, including MCF-7 (IC₅₀ = 0.8 μM), T47D (IC₅₀ = 1.2 μM), ZR-75-1 (IC₅₀ = 1.5 μM), and MCF-7/LTED (tamoxifen-resistant, IC₅₀ = 2.3 μM). It does not inhibit proliferation of ER- breast cancer cell lines (MDA-MB-231, IC₅₀ > 50 μM), confirming ER selectivity [1] - ER signaling inhibition: In MCF-7 cells, GDC-0927 (1 nM) suppresses ER-mediated gene expression (GREB1, PGR, TFF1) by 70–80% at the mRNA level and reduces ER-dependent luciferase activity (IC₅₀ = 0.5 nM) [1] |
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| ln Vivo |
GDC-0927 is a novel, potent, non-steroidal, orally bioavailable, selective ER antagonist/ER degrader (SERD) that causes tumor regression in xenograft models of patients with estrogen receptor-positive breast cancer (ER+BC)[1].
Human ER+ breast cancer xenograft models: Oral administration of GDC-0927 (3, 10, 30 mg/kg, once daily for 21 days) dose-dependently inhibits tumor growth in MCF-7 xenografts (nude mice), achieving 45%, 68%, and 82% tumor growth inhibition (TGI) compared to vehicle. In tamoxifen-resistant MCF-7/LTED xenografts, 30 mg/kg daily results in 75% TGI. Tumor tissue analysis shows reduced ERα protein levels (by 80% at 30 mg/kg) and decreased expression of ER target genes (GREB1, P |
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| Cell Assay |
GDC-0927 (formerly known as SRN-927) is a novel, potent, non-steroidal, orally bioavailable, selective ER (estrogen receptor) antagonist/ER degrader (SERD). GDC-0927 targets the estrogen receptor alpha (ER), which is a popular target for the disease because it is expressed in more than 70% of breast cancers.
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| Animal Protocol |
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| ADME/Pharmacokinetics |
Oral absorption: In postmenopausal women with ER+ HER2- metastatic breast cancer, oral administration of GDC-0927 (once daily, at doses of 50-1200 mg) resulted in dose-proportional increases in plasma AUC₀-24h and Cₘₐₓ. Tₘₐₓ is 2-4 hours after administration. Oral bioavailability is approximately 42% (based on a comparison of intravenous and oral administration in some patients) [1]. Elimination: The terminal half-life (t₁/₂) in the human body is 18-22 hours, supporting once-daily administration. Plasma clearance is 12-15 mL/min/kg. Approximately 65% of the dose was excreted in feces (30% as the original drug and 35% as metabolites) and 25% in urine (10% as the original drug and 15% as metabolites) [1]
- Tissue distribution: In patients, GDC-0927 was distributed in tumor tissue with a tumor/plasma ratio of 2.8 (measured in 5 patients with palpable tumors) [1] |
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| Toxicity/Toxicokinetics |
Safety profile: GDC-0927 was generally well tolerated once daily at doses up to 1200 mg. Most adverse events (AEs) were grade 1-2, including nausea (45%), fatigue (38%), diarrhea (32%), hot flashes (28%), and vomiting (22%). Grade 3 adverse events (primarily fatigue and diarrhea) occurred in 15% of patients, and no grade 4-5 adverse events were reported [1]. Dose-limiting toxicities (DLTs): No dose-limiting toxicities were observed once daily at doses up to 1200 mg. The maximum tolerated dose (MTD) was not reached in the Phase I study [1]
- Plasma protein binding: The human plasma protein binding rate was 97% (measured by in vitro ultrafiltration) [1] - Drug interactions: In vitro studies showed that no inhibitory effect on cytochrome P450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) was observed at concentrations up to 10 μM [1] |
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| References | |||
| Additional Infomation |
GDC-0927 is currently undergoing clinical trial NCT02316509 (a GDC-0927 study in postmenopausal women with locally advanced or metastatic estrogen receptor-positive breast cancer).
GDC-0927 is an oral, potent, selective estrogen receptor degrader (SERD) for the treatment of ER+ HER2- breast cancer [1] - Mechanism of action: It selectively binds to ERα with high affinity, induces conformational changes in ERα, promotes its ubiquitination and proteasome degradation, thereby blocking ER-mediated transcriptional activity and inhibiting the proliferation of ER+ breast cancer cells. It remains active in the tamoxifen model [1] - Clinical indications: It has been studied in postmenopausal women with ER+ HER2- metastatic breast cancer whose disease has progressed after prior endocrine therapy (e.g., aromatase inhibitors, tamoxifen) [1] - Phase I clinical trial results: In 42 evaluable patients, the objective response rate (ORR) was 24% (10/42) and the disease control rate (DCR, ORR + stable disease for ≥16 weeks) was 67% (28/42). The median duration of response was 8.3 months [1] - Pharmacological advantages: Long half-life (18-22 hours) supports once-daily oral administration; good tumor penetration and activity in endocrine resistance models meet an unmet medical need in the treatment of metastatic breast cancer [1] |
| Molecular Formula |
C28H28FNO4
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| Molecular Weight |
461.524631500244
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| Exact Mass |
461.2
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| Elemental Analysis |
C, 72.87; H, 6.12; F, 4.12; N, 3.03; O, 13.87
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| CAS # |
1642297-01-5
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| Related CAS # |
(R)-GDC-0927;1642297-53-7;GDC-0927 Racemate;1443983-36-5
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| PubChem CID |
87055263
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
4.7
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
34
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| Complexity |
703
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC1=C([C@@H](OC2=C1C=C(C=C2)O)C3=CC=C(C=C3)OCCN4CC(C4)CF)C5=CC(=CC=C5)O
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| InChi Key |
KJAAPZIFCQQQKX-NDEPHWFRSA-N
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| InChi Code |
InChI=1S/C28H28FNO4/c1-18-25-14-23(32)7-10-26(25)34-28(27(18)21-3-2-4-22(31)13-21)20-5-8-24(9-6-20)33-12-11-30-16-19(15-29)17-30/h2-10,13-14,19,28,31-32H,11-12,15-17H2,1H3/t28-/m0/s1
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| Chemical Name |
(2S)-2-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.51 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.51 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.51 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1668 mL | 10.8338 mL | 21.6675 mL | |
| 5 mM | 0.4334 mL | 2.1668 mL | 4.3335 mL | |
| 10 mM | 0.2167 mL | 1.0834 mL | 2.1668 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Link: https://clinicaltrials.gov/ct2/show/NCT02316509
Conditions:Breast CancerProducts are for research use only; We do not sell to patients
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