Author: McLean, Nev ; Liang, Jun ; Kleinheinz, Tracy ; Friedman, Lori ; Nannini, Michelle ; Li, Jun ; Liao, Jiangpeng ; Vinogradova, Maia ; Blake, Robert A ; Ray, Nick ; Zhang, Birong ; Mody, Vidhi ; Labadie, Sharada ; Kiefer, James R ; Ran, Yingqing ; Chang, Jae ; Goodacre, Simon ; Hartman, Steven J ; Wang, Tao ; Wai, John ; Zbieg, Jason R ; Sampath, Deepak ; Zhong, Yu ; Ortwine, Daniel F ; Yeap, Kuen ; Metcalfe, Ciara ; Roussel, Fabien ; Lai, Tommy ; Rei Ingalla, Ellen ; Zheng, Xiaoping ; Wang, Xiaojing ; Sambrone, Amy

Fulvestrant is an FDA-approved drug with a dual mechanism of action (MOA), acting as a full antagonist and degrader of the estrogen receptor protein. A significant limitation of fulvestrant is the dosing regimen required for efficacy. Due to its high lipophilicity and poor pharmacokinetic profile, fulvestrant needs to be administered through intramuscular injections which leads to injection site soreness. This route of administration also limits the dose and target occupancy in patients. We envisioned a best-in-class molecule that would function with the same dual MOA as fulvestrant, but with improved physicochemical properties and would be orally bioavailable. Herein we report our progress toward that goal, resulting in a new lead GNE-502 which addressed some of the liabilities of our previously reported lead molecule GNE-149.

26 Aug 2021·Journal of Medicinal ChemistryQ1 · MEDICINE

GDC-9545 (Giredestrant): A Potent and Orally Bioavailable Selective Estrogen Receptor Antagonist and Degrader with an Exceptional Preclinical Profile for ER+ Breast Cancer

Q1 · MEDICINE

Article

Author: Ran, Yingqing ; Sambrone, Amy ; Yeap, Siew Kuen ; Chang, Jae H. ; Li, Jun ; Young, Amy ; Kiefer, James R. ; Vinogradova, Maia ; Zheng, Xiaoping ; Zhang, Birong ; Gelzleichter, Thomas ; Ray, Nicholas C. ; Giltnane, Jennifer M. ; DiPasquale, Antonio G. ; Liang, Jun ; Wang, Tao ; Wang, Xiaojing ; Ingalla, Ellen Rei ; Wertz, Ingrid E. ; Roussel, Fabien ; O’Rourke, Martin G. ; Zbieg, Jason R. ; Lai, Tommy ; Kategaya, Lorn ; Liu, Zhiguo ; Zhou, Wei ; Daly, Stephen ; Oeh, Jason ; Kleinheinz, Tracy ; Hartman, Steven J. ; Nannini, Michelle A. ; White, Jonathan R. ; Sampath, Deepak ; Metcalfe, Ciara ; Ortwine, Daniel F. ; Gill, Matthew ; McLean, Neville ; Labadie, Sharada S. ; Goodacre, Simon ; Zhong, Yu ; Wai, John ; Mody, Vidhi ; Blake, Robert A. ; Friedman, Lori S. ; Guan, Jane ; Liao, Jiangpeng ; Schutt, Leah K.

Breast cancer remains a leading cause of cancer death in women, representing a significant unmet medical need. Here, we disclose our discovery efforts culminating in a clinical candidate, 35 (GDC-9545 or giredestrant). 35 is an efficient and potent selective estrogen receptor degrader (SERD) and a full antagonist, which translates into better antiproliferation activity than known SERDs (1, 6, 7, and 9) across multiple cell lines. Fine-tuning the physiochemical properties enabled once daily oral dosing of 35 in preclinical species and humans. 35 exhibits low drug-drug interaction liability and demonstrates excellent in vitro and in vivo safety profiles. At low doses, 35 induces tumor regressions either as a single agent or in combination with a CDK4/6 inhibitor in an ESR1^Y537S mutant PDX or a wild-type ERα tumor model. Currently, 35 is being evaluated in Phase III clinical trials.

13 Apr 2021·ACS OmegaQ3 · CHEMISTRY

From Pure Antagonists to Pure Degraders of the Estrogen Receptor: Evolving Strategies for the Same Target

Q3 · CHEMISTRY

ReviewOA

Author: Peng, Xianyou ; Kang, Borui ; Mottamal, Madhusoodanan ; Wang, Guangdi

Pure antiestrogens, or selective estrogen receptor degraders (SERDs), have proven to be effective in treating breast cancer that has progressed on tamoxifen and/or aromatase inhibitors. However, the only FDA-approved pure antiestrogen, fulvestrant, is limited in efficacy by its low bioavailability. The search for orally bioavailable SERDs has continued for nearly as long as the clinical history of the injection-only fulvestrant. Oral SERDs that have been developed and tested in patients ranged from nonsteroidal ER binders containing an acrylic acid or amino side chain to bifunctional proteolysis-targeting chimera (PROTAC) pure ER degraders. Structural evolution in the development of oral SERD molecules has been closely associated with quantifiable ER-degrading potency, as seen in the structural comparison analysis of acrylic acid and basic amino side-chain-bearing SERDs. Failure to improve on fulvestrant in the clinical trials by numerous acidic SERDs and early basic SERDs is blamed on tolerability and/or insufficient efficacy, which will likely be overcome by the new-generation basic SERD molecules and PROTAC ER degraders with improved oral bioavailability, low toxicity, and superior efficacy of receptor degradation.

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Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	Preclinical	United States	Xidian University	-

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