7MSA

GDC-9545 in complex with estrogen receptor alpha

7MSA の概要

• エントリーDOI: 10.2210/pdb7msa/pdb
• 分子名称: Estrogen receptor, (2S)-3-(3-hydroxyphenyl)-2-(4-iodophenyl)-4-methyl-2H-1-benzopyran-6-ol, 3-[(1R,3R)-1-(2,6-difluoro-4-{[1-(3-fluoropropyl)azetidin-3-yl]amino}phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-2,2-difluoropropan-1-ol, ... (4 entities in total)
• 機能のキーワード: antagonist, breast cancer, transcription
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 129878.83

構造登録者

Kiefer, J.R.,Vinogradova, M.,Liang, J.,Zbieg, J.R.,Wang, X.,Ortwine, D.F. (登録日: 2021-05-10, 公開日: 2021-06-02, 最終更新日: 2024-05-22)

主引用文献

Liang, J.,Zbieg, J.R.,Blake, R.A.,Chang, J.H.,Daly, S.,DiPasquale, A.G.,Friedman, L.S.,Gelzleichter, T.,Gill, M.,Giltnane, J.M.,Goodacre, S.,Guan, J.,Hartman, S.J.,Ingalla, E.R.,Kategaya, L.,Kiefer, J.R.,Kleinheinz, T.,Labadie, S.S.,Lai, T.,Li, J.,Liao, J.,Liu, Z.,Mody, V.,McLean, N.,Metcalfe, C.,Nannini, M.A.,Oeh, J.,O'Rourke, M.G.,Ortwine, D.F.,Ran, Y.,Ray, N.C.,Roussel, F.,Sambrone, A.,Sampath, D.,Schutt, L.K.,Vinogradova, M.,Wai, J.,Wang, T.,Wertz, I.E.,White, J.R.,Yeap, S.K.,Young, A.,Zhang, B.,Zheng, X.,Zhou, W.,Zhong, Y.,Wang, X.
GDC-9545 (Giredestrant): A Potent and Orally Bioavailable Selective Estrogen Receptor Antagonist and Degrader with an Exceptional Preclinical Profile for ER+ Breast Cancer.
J.Med.Chem., 64:11841-11856, 2021

PubMed Abstract: 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, (GDC-9545 or giredestrant). is an efficient and potent selective estrogen receptor degrader (SERD) and a full antagonist, which translates into better antiproliferation activity than known SERDs (, , , and ) across multiple cell lines. Fine-tuning the physiochemical properties enabled once daily oral dosing of in preclinical species and humans. exhibits low drug-drug interaction liability and demonstrates excellent and safety profiles. At low doses, induces tumor regressions either as a single agent or in combination with a CDK4/6 inhibitor in an ESR1 mutant PDX or a wild-type ERα tumor model. Currently, is being evaluated in Phase III clinical trials.

PubMed: 34251202
DOI: 10.1021/acs.jmedchem.1c00847

実験手法

X-RAY DIFFRACTION (2.24 Å)