{{short description|Discontinued oral cancer remedy}} {{Drugbox | Verifiedfields = | Watchedfields = | verifiedrevid = | IUPAC_name = (2''E'')-3-<nowiki>{</nowiki>4-[(1''E'')-2-(2-chloro-4-fluorophenyl)-1-(1''H''-indazol-5-yl)but-1-en-1-yl]phenyl}prop-2-enoic acid | image = Brilanestrant.svg | image_class = skin-invert-image | width = 250px
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<!--Pharmacokinetic data--> | bioavailability = | protein_bound = | metabolism = | elimination_half-life = | excretion =
<!-- Identifiers --> | CAS_number_Ref = | CAS_number = 1365888-06-7 | CAS_supplemental = | ATCvet = | ATC_prefix = | ATC_suffix = | ATC_supplemental = | PubChem = 56941241 | IUPHAR_ligand = | DrugBank_Ref = | DrugBank = | ChemSpiderID_Ref = | ChemSpiderID = 35308225 | UNII = 9MM2R1A06R | KEGG = D11264 | ChEBI = | ChEMBL =
<!--Chemical data--> | C=26 | H=20 | Cl=1 | F=1 | N=2 | O=2 | 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 | StdInChI_Ref = | StdInChI = 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+ | StdInChIKey_Ref = | StdInChIKey = BURHGPHDEVGCEZ-KJGLQBJMSA-N | synonyms = GDC-0810, ARN-810, RG-6046, RO-7056118 }}
'''Brilanestrant''' (INN; developmental codes '''GDC-0810''', '''ARN-810''', '''RG-6046''', and '''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.<ref name="WHO2016">{{Cite journal |year=2016 |title=Proposed INN: List 115 |url=https://www.who.int/medicines/publications/druginformation/LP_115.pdf |journal=WHO Drug Information |volume=30 |issue=2 |pages=242–357}}</ref><ref name="AdisInsight">{{Cite web |date=12 November 2016 |title=Drug Profile: GDC 0810 |url=https://adisinsight.springer.com/drugs/800037835 |website=AdisInsight}}</ref><ref name="LaiKahraman2015">{{Cite journal |display-authors=6 |vauthors=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 |date=June 2015 |title=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=Journal of Medicinal Chemistry |volume=58 |issue=12 |pages=4888–904 |doi=10.1021/acs.jmedchem.5b00054 |pmid=25879485}}</ref><ref name="JosephDarimont2016">{{Cite journal |display-authors=6 |vauthors=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 |date=July 2016 |title=The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer |journal=eLife |volume=5 |article-number=e15828 |doi=10.7554/eLife.15828 |pmc=4961458 |pmid=27410477 |doi-access=free}}</ref><ref name="pmid25956960">{{Cite journal |date=July 2015 |title=Evaluating an ER Degrader for Breast Cancer |journal=Cancer Discovery |volume=5 |issue=7 |pages=OF15 |doi=10.1158/2159-8290.CD-NB2015-068 |pmid=25956960}}</ref>
Development of brilanestrant was discontinued by Roche in April 2017.<ref name="EndpointsNews">{{Cite news |last=John Carroll |date=27 April 2017 |title=Roche silently whisks away its $1.7B Seragon drug in a Q1 footnote |url=https://endpts.com/roche-silently-whisks-away-its-1-7b-seragon-drug-in-a-q1-footnote/ |access-date=27 April 2017 |publisher=Endpoints News}}</ref> It reached phase II clinical trials for the treatment of breast cancer prior to the discontinuation of its development.<ref name="AdisInsight" /><ref name="pmid25956960" />
==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.<ref name="LaiKahraman2015" /><ref name="JosephDarimont2016" /> Brilanestrant has been found to be active in tamoxifen- and fulvestrant-resistant ''in vitro'' models of human breast cancer.<ref name="pmid25956960" /><ref>{{Cite journal |display-authors=6 |vauthors=Govek SP, Nagasawa JY, Douglas KL, Lai AG, Kahraman M, Bonnefous C, Aparicio AM, Darimont BD, Grillot KL, Joseph JD, Kaufman JA, Lee KJ, Lu N, Moon MJ, Prudente RY, Sensintaffar J, Rix PJ, Hager JH, Smith ND |date=November 2015 |title=Optimization of an indazole series of selective estrogen receptor degraders: Tumor regression in a tamoxifen-resistant breast cancer xenograft |journal=Bioorganic & Medicinal Chemistry Letters |volume=25 |issue=22 |pages=5163–7 |doi=10.1016/j.bmcl.2015.09.074 |pmid=26463130}}</ref> Side effects observed in clinical studies of brilanestrant thus far have included diarrhea, nausea, and fatigue of mostly mild-to-moderate severity.<ref name="pmid25956960" />
Brilanestrant is a structural analogue of etacstil, an earlier combined SERM and SERD that was abandoned in 2001 for commercial reasons.<ref name="pmid26162914">{{Cite journal |vauthors=Wardell SE, Nelson ER, Chao CA, Alley HM, McDonnell DP |year=2015 |title=Evaluation of the pharmacological activities of RAD1901, a selective estrogen receptor degrader |journal=Endocrine-Related Cancer |volume=22 |issue=5 |pages=713–24 |doi=10.1530/ERC-15-0287 |pmc=4545300 |pmid=26162914}}</ref><ref name="uchospitalsgw5638">{{Cite web |date=12 May 2005 |title=Tamoxifen-like drug suggests new ways to selectively block estrogen. |url=http://www.uchospitals.edu/news/2005/20050512-gw5638.html |archive-url=https://web.archive.org/web/20180327181926/http://www.uchospitals.edu/news/2005/20050512-gw5638.html |archive-date=27 March 2018 |access-date=27 October 2016 |publisher=The University of Chicago Medical Center}}</ref><ref>{{Cite journal |vauthors=Dardes RC, O'Regan RM, Gajdos C, Robinson SP, Bentrem D, De Los Reyes A, Jordan VC |date=June 2002 |title=Effects of a new clinically relevant antiestrogen (GW5638) related to tamoxifen on breast and endometrial cancer growth in vivo |journal=Clinical Cancer Research |volume=8 |issue=6 |pages=1995–2001 |pmid=12060645}}</ref>
==See also== * Bazedoxifene * Elacestrant
==References== {{Reflist|2}}
==External links== * [https://adisinsight.springer.com/drugs/800037835 GDC-0810 (brilanestrant) - AdisInsight] * [https://www.gene.com/medical-professionals/pipeline Pipeline - Genentech]
{{Estrogen receptor modulators}}
Category:Abandoned drugs Category:Antiestrogens Category:Chlorobenzene derivatives Category:Fluorobenzene derivatives Category:Hormonal antineoplastic drugs Category:Indazoles Category:Selective estrogen receptor degraders Category:Selective estrogen receptor modulators Category:Triphenylethylenes