Selective Targeting of GSPT1 by CC-90009: Unleashing Tumoricidal Effects in Acute Myeloid Leukemia

A novel cereblon E3 ligase modulator, CC-90009, has been identified to selectively target the GSPT1 protein, leading to its degradation and subsequent growth inhibition in AML cell lines and patient samples. The compound was discovered through a cell-based screening process involving 11 human AML cell lines with common mutations, showing potent antiproliferative effects with IC50 values between 3 to 75 nM. CC-90009 induced apoptosis in 5 AML cell lines within 16 to 48 hours and demonstrated a rapid and efficient killing of leukemic cells in patient samples, with an average EC50 of 21 nM.

The activity of CC-90009 was found to be CRBN-dependent, as CRISPR/Cas9-mediated gene editing to remove CRBN negated its effects. Mass spectrometry confirmed the selective reduction of GSPT1 levels in treated AML cells, with no significant impact on other proteins. The degradation process was blocked by proteasome inhibitors or inactivation of the CRL4^CRBN ubiquitin ligase complex. Overexpression of a GSPT1 mutant resistant to degradation rendered cells resistant to CC-90009, while partial knockdown of GSPT1 via RNAi enhanced the compound's effects.

Mechanistically, the degradation of GSPT1 by CC-90009 activates the integrated stress response pathway, which is linked to the induction of apoptosis and inhibition of cell proliferation. CC-90009 is a first-in-class GSPT1 degrader that is currently in clinical development, with its degradation of GSPT1 being crucial for inducing apoptosis and antiproliferative activity. The compound's significant antiproliferative effect in over 80% of human AML cell lines and blasts supports the ongoing phase 1 clinical study in relapsed or refractory AML patients.