Brilanestrant Explained

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]

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.

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. Brilanestrant has been found to be active in tamoxifen- and fulvestrant-resistant in vitro models of human breast cancer.[7] Side effects observed in clinical studies of brilanestrant thus far have included diarrhea, nausea, and fatigue of mostly mild-to-moderate severity.

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

External links

Notes and References

  1. Proposed INN: List 115 . WHO Drug Information . 2016 . 30 . 2 . 242–357 .
  2. Web site: Drug Profile: GDC 0810 . AdisInsight . 12 November 2016 .
  3. 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 . 6 . 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 . June 2015 . 25879485 . 10.1021/acs.jmedchem.5b00054 .
  4. 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 . 6 . The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer . eLife . 5 . e15828 . July 2016 . 27410477 . 4961458 . 10.7554/eLife.15828 . free .
  5. Evaluating an ER Degrader for Breast Cancer . Cancer Discovery . 5 . 7 . OF15 . July 2015 . 25956960 . 10.1158/2159-8290.CD-NB2015-068 .
  6. News: Roche silently whisks away its $1.7B Seragon drug in a Q1 footnote . John Carroll . 27 April 2017 . 27 April 2017 . Endpoints News.
  7. 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 . 6 . 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 . November 2015 . 26463130 . 10.1016/j.bmcl.2015.09.074 .
  8. Wardell SE, Nelson ER, Chao CA, Alley HM, McDonnell DP . Evaluation of the pharmacological activities of RAD1901, a selective estrogen receptor degrader . Endocrine-Related Cancer . 22 . 5 . 713–24 . 2015 . 26162914 . 4545300 . 10.1530/ERC-15-0287 .
  9. Web site: Tamoxifen-like drug suggests new ways to selectively block estrogen.. The University of Chicago Medical Center. 12 May 2005. 27 October 2016. 27 March 2018. https://web.archive.org/web/20180327181926/http://www.uchospitals.edu/news/2005/20050512-gw5638.html. dead.
  10. Dardes RC, O'Regan RM, Gajdos C, Robinson SP, Bentrem D, De Los Reyes A, Jordan VC . 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 . June 2002 . 12060645 .

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