CC-90009 is a modulator of the E3 ligase cereblon.1 It binds to cereblon and enhances the protein-protein interaction between cereblon and the cell cycle regulator and translation termination factor G1 to S phase transition 1 (GSPT1) to induce ubiquitination and proteasomal degradation of GSPT1. CC-90009 (0.01-10 ?M) inhibits the growth of U937 cells in a concentration-dependent manner, an effect that can be reversed by overexpression of the GSPT1 stabilization mutant GSPT1G575N. It inhibits cell growth in a panel of acute myeloid leukemia (AML) cells, an effect that can be reversed by hyperactivation of the mammalian target of rapamycin (mTOR) pathway or knockout of the interleukin enhancer binding factor 2 (ILF2) and ILF3 heterodimeric complex to decrease production of full-length cereblon. CC-90009 induces intratumor GSPT1 degradation in AML mouse xenograft models and decreases leukemic engraftment of 35 patient-derived AML samples in NOD.SCID mice.
1.Surka, C., Jin, L., Mbong, M., et al.CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cellsBlood137(5)6610677(2021)