9ODR

Structure of CRBN TBD bound to compound C1

This is a non-PDB format compatible entry.

Summary for 9ODR

• Entry DOI: 10.2210/pdb9odr/pdb
• Descriptor: Protein cereblon, (3S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione, ZINC ION, ... (4 entities in total)
• Functional Keywords: protein degrader, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 50919.44

Authors

Strickland, C.,Rice, C. (deposition date: 2025-04-27, release date: 2025-05-28, Last modification date: 2025-06-25)

Primary citation

Xu, G.,Havens, C.G.,Deng, Q.,Lowenstein, C.,Samanta, D.,Vidal, B.,Behshad, E.,Russell, M.,Orth, P.,Rice, C.T.,Nagilla, R.,Kirchhoff, P.,Chen, Z.,Rej, R.K.,Acharyya, R.K.,Wu, D.,Wang, S.,Zhang, W.,Wu, W.,Jolivette, L.,Strickland, C.,Sui, Z.,Mohammad, H.P.,Zhang, X.,Priestley, E.S.
Discovery and Characterization of PVTX-321 as a Potent and Orally Bioavailable Estrogen Receptor Degrader for ER+/HER2- Breast Cancer.
J.Med.Chem., 68:11299-11321, 2025

PubMed Abstract: Estrogen receptor α (ERα) is a key therapeutic target in ER+/HER2- breast cancer, but mutations drive resistance to endocrine therapies. Heterobifunctional degraders (HBDs) targeting ERα offer a promising strategy to overcome this resistance. Here, we report PVTX-321 (), a potent ER HBD derived from a novel spirocyclic cereblon ligand and an ERα binder. PVTX-321 achieves a DC of 0.15 nM in MCF-7 cells and acts as a strong antagonist (IC = 59 nM), suppressing proliferation in ERα+ cell lines, including mutant variants (Y537S, D538G). It demonstrates favorable oral bioavailability, dose-dependent ERα degradation and induces tumor regression at 10 mg/kg (QD) in MCF-7 xenografts. With minimal CYP inhibition and a strong preclinical safety profile, PVTX-321 is a promising candidate for advancing ER+/HER2- breast cancer treatment.

PubMed: 40366756
DOI: 10.1021/acs.jmedchem.5c00223

Experimental method

X-RAY DIFFRACTION (2.42 Å)