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].
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References |
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] |