ERD-308   Click here for help

GtoPdb Ligand ID: 10565

Synonyms: compound 32 [PMID: 30990042] | ERD308
Compound class: Synthetic organic
Comment: ERD-308 is a small-molecule ERα degrader that was designed using the proteolysis targeting chimeras (PROTAC) model [1]. It is a hybrid molecule that links together an ERα antagonist (a derivative of raloxifene) and a VHL ligand that engages the VHL E3 ligase to direct ERα receptors for ubiquitination and proteasomal degradation.
2D Structure
Click here for help
Click here for structure editor
Physico-chemical Properties
Click here for help
Hydrogen bond acceptors 11
Hydrogen bond donors 5
Rotatable bonds 26
Topological polar surface area 247.34
Molecular weight 1003.42
XLogP 7.84
No. Lipinski's rules broken 3
Click here for help
Canonical SMILES CCN(CCOc1ccc(cc1)C(=O)c1c(sc2c1ccc(c2)O)c1ccc(cc1)O)CCCCCOCC(=O)NC(C(C)(C)C)C(=O)N1CC(CC1C(=O)NC(c1ccc(cc1)c1scnc1C)C)O
Isomeric SMILES CCN(CCOc1ccc(cc1)C(=O)c1c(sc2c1ccc(c2)O)c1ccc(cc1)O)CCCCCOCC(=O)N[C@@H](C(C)(C)C)C(=O)N1C[C@@H](C[C@H]1C(=O)N[C@H](c1ccc(cc1)c1scnc1C)C)O
InChI InChI=1S/C55H65N5O9S2/c1-7-59(26-28-69-43-22-17-37(18-23-43)49(65)48-44-24-21-41(62)30-46(44)71-51(48)39-15-19-40(61)20-16-39)25-9-8-10-27-68-32-47(64)58-52(55(4,5)6)54(67)60-31-42(63)29-45(60)53(66)57-34(2)36-11-13-38(14-12-36)50-35(3)56-33-70-50/h11-24,30,33-34,42,45,52,61-63H,7-10,25-29,31-32H2,1-6H3,(H,57,66)(H,58,64)/t34-,42+,45-,52+/m0/s1
Bioactivity Comments
ERD-308 induces more complete ER degradation than the approved ER degrader (SERD) fulvestrant [1] which targets ERα for proteasome-dependent degradation but via a different mechanism (protein mis-folding) to PROTACs. SERDs only achieve partial degradation of the ER protein, whereas ERD-308 can induce almost complete ER degradation at concentrations as low as 5 nM in cell lines. The DC50 of ERD-308 for ERα is 0.17 nM in MCF-7 cells, and 0.43 nM in T47D cells. It binds the VHL protein with an IC50 of 196 nM.
Selectivity at nuclear hormone receptors
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
Estrogen receptor-α Hs Antagonist Antagonist - - - 1