Giredestrant (GDC-9545)

Catalog No.	APIM050399
Product Name	Giredestrant (GDC-9545)

Description

APIM050399: Giredestrant (GDC-9545), Non-Steroidal Estrogen Receptor (ER) Ligand

CAS No.: 1953133-47-5 (CAS No. 2407529-33-1 for giredestrant tartrate)
IUPAC/Chemical Name: 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol
Molecular Formula: C₂₇H₃₁F₅N₄O
Molecular Weight: 522.55
Purity: >99.5% purity
QC: HPLC-MS, chiral HPLC and quantitative elemental analysis.
Solubility: Soluble in DMSO
Storage: Store at 0 °C (short term), -20 °C (long term), Desiccated

Note: Please contact us for COA, Spectra, and SDS information.

Background:

Giredestrant (GDC-9545, CAS No.: 1953133-47-5), a non-steroidal estrogen receptor (ER) ligand, is an orally active and selective estrogen receptor degrader/downregulator (SERD) with potential antineoplastic activity. Giredestrant potently competes with Estradiol for binding and induces a conformational change within the ER ligand binding domain. Upon oral administration, GDC-9545 specifically targets and binds to ER and induces a conformational change to promote ER degradation, which prevents ER-mediated signaling and inhibits both the growth and survival of ER-expressing cancer cells.

Orally given, giredestrant delivers a strong clinical efficacy and safety profile and has shown superior pre-clinical potency over other SERDs in development. The oral administration of giredestrant has the potential to transform the treatment experience for patients, offering greater convenience and a less painful option compared to therapies administered via intramuscular injection.

Giredestrant has a comprehensive development programme across a broad range of settings and treatment combinations for patients with HR-positive, HER2-negative breast cancer. A standardised once-daily 30mg dose has been selected for the giredestrant development programme, both as a monotherapy and in combination studies.

Selective estrogen receptor degrader Giredestrant (GDC-9545) was synthesized in a longest linear sequence of six steps in 37% overall yield with 99% HPLC purity without chromatographic purification. The synthesis features a Friedel–Crafts indole functionalization, a strain-release aminoazetidine formation, a diastereoselective Pictet–Spengler reaction (98% yield, 95:5 dr) to assemble the tetrahydrocarboline core, and a highly efficient Pd-catalyzed C–N coupling (90% yield) using [t-BuBrettPhos Pd(allyl)]OTf as the catalyst and DBU as the base.[5]

Target: estrogen receptor (ER)

In Vitro: Giredestrant (GDC-9545) is a novel estrogen receptor (ER) antagonist that combines desirable mechanistic and pre-clinical DMPK attributes. The highly potent in-vivo efficacy of Giredestrant likely arises due to the particular combination of high binding potency, full suppression of ER signaling, and an improved DMPK profile.[1]

How to make giredestrant stock solutions in vitro?

Reference:

[1]. Metcalfe, C. et al. “Abstract P5-04-07: GDC-9545: A novel ER antagonist and clinical candidate that combines desirable mechanistic and pre-clinical DMPK attributes”, 2019, 79, P5-04-07.

[2]. Liang, J. et al., “GDC-9545 (Giredestrant): A Potent and Orally Bioavailable Selective Estrogen Receptor Antagonist and Degrader with an Exceptional Preclinical Profile for ER+ Breast Cancer”, J. Med. Chem. 2021, 64, 11841–11856.

[3]. Tucker, N. “Adjuvant Giredestrant Goes Up Against Third-Generation Endocrine Therapies in ER+/HER2- Early Breast Cancer” Target. Oncol. 2021.

[4]. “A Study Evaluating the Efficacy and Safety of Giredestrant Combined with Palbociclib Compared with Letrozole Combined with Palbociclib in Participants with Estrogen Receptor-Positive, HER2-Negative Locally Advanced or Metastatic Breast Cancer.” Clinicaltrials.gov 2021.

[5]. Xu, J. et al. “First-Generation Asymmetric Synthesis of the Selective Estrogen Receptor Degrader GDC-9545 (Giredestrant) Featuring a Highly Efficient Pictet–Spengler Reaction and a C–N Coupling Reaction” Org. Process Res. Dev. 2021, ASAP.

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