CC-885   Click here for help

GtoPdb Ligand ID: 9224

Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: Structural studies have shown that thalidomide class immunomodulatory drugs bind in a shallow hydrophobic pocket on the surface of cereblon, that is mediated by a glutarimide ring of the ligand. Binding of small molecules to cereblon can alter its substrate specificity [1]. Thalidomide and its related drugs enhance recruitment of Ikaros and Aiolos to the E3 ubiquitin ligase complex. CC-885 has a different mechanism of action compared to thalidomide, lenalidomide and pomalidomide. The anti-tumour activity of CC-885 is mediated through the cereblon-dependent ubiquitination and degradation of the translation termination factor GSPT1. Patient-derived acute myeloid leukaemia tumour cells exhibit high sensitivity to CC-885, indicating the clinical potential of this mechanism [2].
2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 8
Hydrogen bond donors 3
Rotatable bonds 6
Topological polar surface area 107.61
Molecular weight 440.13
XLogP 1.83
No. Lipinski's rules broken 0
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Canonical SMILES O=C(Nc1ccc(c(c1)Cl)C)NCc1ccc2c(c1)CN(C2=O)C1CCC(=O)NC1=O
Isomeric SMILES O=C(Nc1ccc(c(c1)Cl)C)NCc1ccc2c(c1)CN(C2=O)C1CCC(=O)NC1=O
InChI InChI=1S/C22H21ClN4O4/c1-12-2-4-15(9-17(12)23)25-22(31)24-10-13-3-5-16-14(8-13)11-27(21(16)30)18-6-7-19(28)26-20(18)29/h2-5,8-9,18H,6-7,10-11H2,1H3,(H2,24,25,31)(H,26,28,29)
1. Hansen JD, Condroski K, Correa M, Muller G, Man HW, Ruchelman A, Zhang W, Vocanson F, Crea T, Liu W et al.. (2018)
Protein Degradation via CRL4CRBN Ubiquitin Ligase: Discovery and Structure-Activity Relationships of Novel Glutarimide Analogs That Promote Degradation of Aiolos and/or GSPT1.
J Med Chem, 61 (2): 492-503. [PMID:28358507]
2. Matyskiela ME, Lu G, Ito T, Pagarigan B, Lu CC, Miller K, Fang W, Wang NY, Nguyen D, Houston J et al.. (2016)
A novel cereblon modulator recruits GSPT1 to the CRL4(CRBN) ubiquitin ligase.
Nature, 535 (7611): 252-7. [PMID:27338790]