Brilanestrant

Brilanestrant (INN) (developmental code names GDC-0810, ARN-810, RG-6046, RO-7056118) is a nonsteroidal combined selective estrogen receptor modulator (SERM) and selective estrogen receptor degrader (SERD) that was discovered by Aragon Pharmaceuticals and was under development by Genentech for the treatment of locally advanced or metastatic estrogen receptor (ER)-positive breast cancer.[1][2][3][4][5]

Brilanestrant
Clinical data
Other namesGDC-0810, ARN-810, RG-6046, RO-7056118
Routes of
administration		Oral
Identifiers
IUPAC name
  • (2E)-3-{4-[(1E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl]phenyl}prop-2-enoic acid
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
Chemical and physical data
FormulaC26H20ClFN2O2
Molar mass446.91 g·mol−1
3D model (JSmol)
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
InChI
  • 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+
  • Key:BURHGPHDEVGCEZ-KJGLQBJMSA-N

Development of brilanestrant was discontinued by Roche in April 2017.[6] It reached phase II clinical trials for the treatment of breast cancer prior to the discontinuation of its development.[2][5]

Mechanism of action

Similarly to tamoxifen, a SERM, brilanestrant shows some capacity to activate the ER in certain contexts and possesses weak estrogenic activity in the rat uterus, and unlike fulvestrant, which is currently the only SERD to have been marketed, brilanestrant is not a steroid and is orally bioavailable and does not need to be administered by intramuscular injection.[3][4] Brilanestrant has been found to be active in tamoxifen- and fulvestrant-resistant in vitro models of human breast cancer.[5][7] Side effects observed in clinical studies of brilanestrant thus far have included diarrhea, nausea, and fatigue of mostly mild-to-moderate severity.[5]

Brilanestrant is a structural analogue of etacstil, an earlier combined SERM and SERD that was abandoned in 2001 for commercial reasons.[8][9][10]

See also

References
  1. "Proposed INN: List 115" (PDF). WHO Drug Information. 30 (2): 242–357. 2016.
  2. "Drug Profile: GDC 0810". AdisInsight. 12 November 2016.
  3. Lai A, Kahraman M, Govek S, Nagasawa J, Bonnefous C, Julien J, et al. (June 2015). "Identification of GDC-0810 (ARN-810), an Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) that Demonstrates Robust Activity in Tamoxifen-Resistant Breast Cancer Xenografts". Journal of Medicinal Chemistry. 58 (12): 4888–904. doi:10.1021/acs.jmedchem.5b00054. PMID 25879485.
  4. Joseph JD, Darimont B, Zhou W, Arrazate A, Young A, Ingalla E, et al. (July 2016). "The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer". eLife. 5: e15828. doi:10.7554/eLife.15828. PMC 4961458. PMID 27410477.
  5. "Evaluating an ER Degrader for Breast Cancer". Cancer Discovery. 5 (7): OF15. July 2015. doi:10.1158/2159-8290.CD-NB2015-068. PMID 25956960.
  6. John Carroll (27 April 2017). "Roche silently whisks away its $1.7B Seragon drug in a Q1 footnote". Endpoints News. Retrieved 27 April 2017.
  7. Govek SP, Nagasawa JY, Douglas KL, Lai AG, Kahraman M, Bonnefous C, et al. (November 2015). "Optimization of an indazole series of selective estrogen receptor degraders: Tumor regression in a tamoxifen-resistant breast cancer xenograft". Bioorganic & Medicinal Chemistry Letters. 25 (22): 5163–7. doi:10.1016/j.bmcl.2015.09.074. PMID 26463130.
  8. Wardell SE, Nelson ER, Chao CA, Alley HM, McDonnell DP (2015). "Evaluation of the pharmacological activities of RAD1901, a selective estrogen receptor degrader". Endocrine-Related Cancer. 22 (5): 713–24. doi:10.1530/ERC-15-0287. PMC 4545300. PMID 26162914.
  9. "Tamoxifen-like drug suggests new ways to selectively block estrogen". The University of Chicago Medical Center. 12 May 2005.
  10. Dardes RC, O'Regan RM, Gajdos C, Robinson SP, Bentrem D, De Los Reyes A, Jordan VC (June 2002). "Effects of a new clinically relevant antiestrogen (GW5638) related to tamoxifen on breast and endometrial cancer growth in vivo". Clinical Cancer Research. 8 (6): 1995–2001. PMID 12060645.
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