9ods
From Proteopedia
Structure of CRBN TBD bound to compound C3
Structural highlights
DiseaseCRBN_HUMAN Autosomal recessive nonsyndromic intellectual deficit;Distal monosomy 3p. The disease is caused by mutations affecting the gene represented in this entry. FunctionCRBN_HUMAN Component of some DCX (DDB1-CUL4-X-box) E3 protein ligase complex, a complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins and is required for limb outgrowth and expression of the fibroblast growth factor FGF8. In the complex, may act as a substrate receptor. Regulates the assembly and neuronal surface expression of large-conductance calcium-activated potassium channels in brain regions involved in memory and learning via its interaction with KCNT1.[1] [2] Publication Abstract from PubMedEstrogen receptor alpha (ERalpha) is a key therapeutic target in ER+/HER2- breast cancer, but ESR1 mutations drive resistance to endocrine therapies. Heterobifunctional degraders (HBDs) targeting ERalpha offer a promising strategy to overcome this resistance. Here, we report PVTX-321 (16a), a potent ER HBD derived from a novel spirocyclic cereblon ligand and an ERalpha binder. PVTX-321 achieves a DC(50) of 0.15 nM in MCF-7 cells and acts as a strong antagonist (IC(50) = 59 nM), suppressing proliferation in ERalpha+ cell lines, including mutant variants (Y537S, D538G). It demonstrates favorable oral bioavailability, dose-dependent ERalpha degradation in vivo 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. Discovery and Characterization of PVTX-321 as a Potent and Orally Bioavailable Estrogen Receptor Degrader for ER+/HER2- Breast Cancer.,Xu G, Havens CG, Deng Q, Lowenstein C, Samanta D, Vidal B, Behshad E, Russell M, Orth P, Rice CT, Nagilla R, Kirchhoff P, Chen Z, Rej RK, Acharyya RK, Wu D, Wang S, Zhang W, Wu W, Jolivette L, Strickland C, Sui Z, Mohammad HP, Zhang X, Priestley ES J Med Chem. 2025 May 14. doi: 10.1021/acs.jmedchem.5c00223. PMID:40366756[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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