7MSA
GDC-9545 in complex with estrogen receptor alpha
Summary for 7MSA
| Entry DOI | 10.2210/pdb7msa/pdb |
| Descriptor | 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) |
| Functional Keywords | antagonist, breast cancer, transcription |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 129878.83 |
| Authors | Kiefer, J.R.,Vinogradova, M.,Liang, J.,Zbieg, J.R.,Wang, X.,Ortwine, D.F. (deposition date: 2021-05-10, release date: 2021-06-02, Last modification date: 2024-05-22) |
| Primary citation | 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 Cited by 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: 34251202DOI: 10.1021/acs.jmedchem.1c00847 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.24 Å) |
Structure validation
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