6CHW

Estrogen Receptor Alpha Y537S covalently bound to antagonist H3B-5942.

Summary for 6CHW

• Entry DOI: 10.2210/pdb6chw/pdb
• Descriptor: Estrogen receptor, 4-[(2-{4-[(1E)-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl]phenoxy}ethyl)amino]-N,N-dimethylbutanamide, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: nuclear hormone receptor, covalent antagonist, activating mutation, breast cancer, nuclear protein, nuclear protein-antagonist complex, nuclear protein/antagonist
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 28796.94

Authors

Larsen, N.A. (deposition date: 2018-02-23, release date: 2018-03-21, Last modification date: 2024-10-23)

Primary citation

Puyang, X.,Furman, C.,Zheng, G.Z.,Wu, Z.J.,Banka, D.,Aithal, K.,Agoulnik, S.,Bolduc, D.M.,Buonamici, S.,Caleb, B.,Das, S.,Eckley, S.,Fekkes, P.,Hao, M.H.,Hart, A.,Houtman, R.,Irwin, S.,Joshi, J.J.,Karr, C.,Kim, A.,Kumar, N.,Kumar, P.,Kuznetsov, G.,Lai, W.G.,Larsen, N.,Mackenzie, C.,Martin, L.A.,Melchers, D.,Moriarty, A.,Nguyen, T.V.,Norris, J.,O'Shea, M.,Pancholi, S.,Prajapati, S.,Rajagopalan, S.,Reynolds, D.J.,Rimkunas, V.,Rioux, N.,Ribas, R.,Siu, A.,Sivakumar, S.,Subramanian, V.,Thomas, M.,Vaillancourt, F.H.,Wang, J.,Wardell, S.,Wick, M.J.,Yao, S.,Yu, L.,Warmuth, M.,Smith, P.G.,Zhu, P.,Korpal, M.
Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ER alphaWTand ER alphaMUTBreast Cancer.
Cancer Discov, 8:1176-1193, 2018

PubMed Abstract: Mutations in estrogen receptor alpha (ERα) that confer resistance to existing classes of endocrine therapies are detected in up to 30% of patients who have relapsed during endocrine treatments. Because a significant proportion of therapy-resistant breast cancer metastases continue to be dependent on ERα signaling, there remains a critical need to develop the next generation of ERα antagonists that can overcome aberrant ERα activity. Through our drug-discovery efforts, we identified H3B-5942, which covalently inactivates both wild-type and mutant ERα by targeting Cys530 and enforcing a unique antagonist conformation. H3B-5942 belongs to a class of ERα antagonists referred to as selective estrogen receptor covalent antagonists (SERCA). comparisons of H3B-5942 with standard-of-care (SoC) and experimental agents confirmed increased antagonist activity across a panel of ERα and ERα cell lines. , H3B-5942 demonstrated significant single-agent antitumor activity in xenograft models representing ERα and ERα breast cancer that was superior to fulvestrant. Lastly, H3B-5942 potency can be further improved in combination with CDK4/6 or mTOR inhibitors in both ERα and ERα cell lines and/or tumor models. In summary, H3B-5942 belongs to a class of orally available ERα covalent antagonists with an improved profile over SoCs. Nearly 30% of endocrine therapy-resistant breast cancer metastases harbor constitutively activating mutations in ERα. SERCA H3B-5942 engages C530 of both ERα and ERα, promotes a unique antagonist conformation, and demonstrates improved and activity over SoC agents. Importantly, single-agent efficacy can be further enhanced by combining with CDK4/6 or mTOR inhibitors. .

PubMed: 29991605
DOI: 10.1158/2159-8290.CD-17-1229

Experimental method

X-RAY DIFFRACTION (1.89 Å)