Giredestrant

Giredestrant
Identifiers
	IUPAC name 3-[(1R,3R)-1-[2,6-difluoro-4-[[1-(3-fluoropropyl)azetidin-3-yl]amino]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2,2-difluoro-propan-1-ol;
CAS Number	1953133-47-5;
PubChem CID	121410806;
UNII	28P3DU6DB3;
KEGG	D11961;
ChEMBL	ChEMBL4650316;
Chemical and physical data
Formula	C27H31F5N4O
Molar mass	522.564 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C[C@@H]1CC2=C([C@H](N1CC(CO)(F)F)C3=C(C=C(C=C3F)NC4CN(C4)CCCF)F)NC5=CC=CC=C25;
	InChI InChI=InChI=1S/C27H31F5N4O/c1-16-9-20-19-5-2-3-6-23(19)34-25(20)26(36(16)14-27(31,32)15-37)24-21(29)10-17(11-22(24)30)33-18-12-35(13-18)8-4-7-28/h2-3,5-6,10-11,16,18,26,33-34,37H,4,7-9,12-15H2,1H3/t16-,26-/m1/s1; Key:GQCXHIKRWBIQMD-AKJBCIBTSA-N;

Giredestrant is an investigational oral selective estrogen receptor degrader (SERD) being developed for the treatment of estrogen receptor-positive (ER+) breast cancer.^[1]^[2] It is a potent, nonsteroidal compound that antagonizes estrogen effects by competitively binding to both wild-type and mutant estrogen receptors with nanomolar potency.^[1]^[3] Giredestrant works by inducing an inactive conformation of the estrogen receptor ligand-binding domain and promoting proteasome-mediated degradation of the receptor protein.^[1]^[4]^[5]

Research

In clinical trials, giredestrant has been evaluated in patients with ER+ breast cancer, including those with ESR1 mutations, both as a single agent and in combination with other therapies.^[2]^[6] Its orally bioavailable.^[3]^[4]

References

^ ^a ^b ^c "Giredestrant (GDC-9545)". NCI Formulatry. U.S. National Cancer Institute.
^ ^a ^b Malhi V, Agarwal P, Gates MR, Liu L, Wang J, De Bruyn T, et al. (December 2023). "Optimizing Early-stage Clinical Pharmacology Evaluation to Accelerate Clinical Development of Giredestrant in Advanced Breast Cancer". Cancer Research Communications. 3 (12): 2551–2559. doi:10.1158/2767-9764.CRC-23-0324. PMC 10722959. PMID 38019116.
^ ^a ^b "A clinical study to compare giredestrant with fulvestrant, both combined with a targeted therapy (CDK4/6 inhibitor) in people with ER‑positive, HER2-negative breast cancer that has come back after adjuvant hormone therapy". Roche.
^ ^a ^b Jhaveri KL, Bellet M, Turner NC, Loi S, Bardia A, Boni V, et al. (February 2024). "Phase Ia/b Study of Giredestrant ± Palbociclib and ± Luteinizing Hormone-Releasing Hormone Agonists in Estrogen Receptor-Positive, HER2-Negative, Locally Advanced/Metastatic Breast Cancer". Clinical Cancer Research. 30 (4): 754–766. doi:10.1158/1078-0432.CCR-23-1796. PMC 10870118. PMID 37921755.
^ Liang J, Zbieg JR, Blake RA, Chang JH, Daly S, DiPasquale AG, et al. (August 2021). "GDC-9545 (Giredestrant): A Potent and Orally Bioavailable Selective Estrogen Receptor Antagonist and Degrader with an Exceptional Preclinical Profile for ER+ Breast Cancer". Journal of Medicinal Chemistry. 64 (16): 11841–11856. doi:10.1021/acs.jmedchem.1c00847. PMID 34251202.
^ Lawrence L (25 July 2024). "Giredestrant Bests Anastrozole in ER+, HER2- Early Breast Cancer".

Gheysen M, Punie K, Wildiers H, Neven P (November 2024). "Oral SERDs changing the scenery in hormone receptor positive breast cancer, a comprehensive review". Cancer Treatment Reviews. 130: 102825. doi:10.1016/j.ctrv.2024.102825. PMID 39293125.
Guglielmi G, Del Re M, Gol LS, Bengala C, Danesi R, Fogli S (April 2024). "Pharmacological insights on novel oral selective estrogen receptor degraders in breast cancer". European Journal of Pharmacology. 969: 176424. doi:10.1016/j.ejphar.2024.176424. PMID 38402929.
Garcia-Fructuoso I, Gomez-Bravo R, Schettini F (November 2022). "Integrating new oral selective oestrogen receptor degraders in the breast cancer treatment". Current Opinion in Oncology. 34 (6): 635–642. doi:10.1097/CCO.0000000000000892. PMID 36000362.
Chen YC, Yu J, Metcalfe C, De Bruyn T, Gelzleichter T, Malhi V, et al. (June 2022). "Latest generation estrogen receptor degraders for the treatment of hormone receptor-positive breast cancer". Expert Opinion on Investigational Drugs. 31 (6): 515–529. doi:10.1080/13543784.2021.1983542. PMID 34694932.

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[nciformulary-1] "Giredestrant (GDC-9545)". NCI Formulatry. U.S. National Cancer Institute.

[Malhi_2023-2] Malhi V, Agarwal P, Gates MR, Liu L, Wang J, De Bruyn T, et al. (December 2023). "Optimizing Early-stage Clinical Pharmacology Evaluation to Accelerate Clinical Development of Giredestrant in Advanced Breast Cancer". Cancer Research Communications. 3 (12): 2551–2559. doi:10.1158/2767-9764.CRC-23-0324. PMC 10722959. PMID 38019116.

[Roche-3] "A clinical study to compare giredestrant with fulvestrant, both combined with a targeted therapy (CDK4/6 inhibitor) in people with ER‑positive, HER2-negative breast cancer that has come back after adjuvant hormone therapy". Roche.

[Jhaveri_2024-4] Jhaveri KL, Bellet M, Turner NC, Loi S, Bardia A, Boni V, et al. (February 2024). "Phase Ia/b Study of Giredestrant ± Palbociclib and ± Luteinizing Hormone-Releasing Hormone Agonists in Estrogen Receptor-Positive, HER2-Negative, Locally Advanced/Metastatic Breast Cancer". Clinical Cancer Research. 30 (4): 754–766. doi:10.1158/1078-0432.CCR-23-1796. PMC 10870118. PMID 37921755.

[Liang_2021-5] Liang J, Zbieg JR, Blake RA, Chang JH, Daly S, DiPasquale AG, et al. (August 2021). "GDC-9545 (Giredestrant): A Potent and Orally Bioavailable Selective Estrogen Receptor Antagonist and Degrader with an Exceptional Preclinical Profile for ER+ Breast Cancer". Journal of Medicinal Chemistry. 64 (16): 11841–11856. doi:10.1021/acs.jmedchem.1c00847. PMID 34251202.

[Lawrence_2024-6] Lawrence L (25 July 2024). "Giredestrant Bests Anastrozole in ER+, HER2- Early Breast Cancer".

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Research

References

Further reading