Modulator of the cullin ring ligase 4-cereblon E3 ubiquitin ligase complex that specifically targets GSPT1 (G1 to S phase transition 1; EC 50 = 9 nM; also known as eRF3a) instead of Ikaros (IKZF1) and Aiolos (IKZF3). It rapidly induced apoptosis and reduced leukemia engraftment and leukemia stem...
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Modulator of the cullin ring ligase 4-cereblon E3 ubiquitin ligase complex that specifically targets GSPT1 (G1 to S phase transition 1; EC 50 = 9 nM; also known as eRF3a) instead of Ikaros (IKZF1) and Aiolos (IKZF3). It rapidly induced apoptosis and reduced leukemia engraftment and leukemia stem cells across a wide spectrum of acute myeloid leukemia xenograft patient samples including refractory/relapsed cases. The anti-AML activity of CC-90009 was shown to be regulated by multiple signaling pathways including the ILF/ILF3 complex, mTOR, and the integrated stress response. CC-90009 was able to potentiate premature termination codon (PTC; 11% of all genetic lesions in patients with inherited diseases contain this type of mutation) readthrough by aminoglycosides via degradation of eukaryotic release factors 1 (eRF1) and 3 (eRF3a/b) in various heritable disease models. It was also able to enhance aminoglycoside PTC readthrough of the mutated retinoblastoma (RB1) gene in MDA-MB-436 breast carcinoma cells and SW1783 astrocytoma cells
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