Blood: New CRBN E3 connective enzyme regulator CC-90009, targeted to promote leukemia stem cell apoptosis

Center point: CC-90009 selective degradation of GSPT1, which can lead to acute AML apoptosis and eliminate the source of the disease LSC.
AML activity of CC-90009 is regulated by ilF2/ILF3 complex, mTOR signal path and integrated stress response path.
many clinically effective drugs have been developed by re-using the CUL4-DDB1-CRBN-RBX1 (CRL4CRBN) E3 Ubigan connective enzyme complex with molecular gel degradation agents to eliminate pathogenic proteins.
study, Christine and others identified a state-of-the-art GSPT1 selective brain protein E3 connective enzyme regulator CC-90009.
biopics, structure and molecular characterization show that CC-90009 is combined with CRL4CRBN to selectively target GSPT1 for ubiquitinization and protease degradation.
GSPT1 with CC-90009 can quickly induce ANL apoptosis and reduce leukemia implants and leukemia stem cells (LSCs) in primary patients.
the effect molecules of the CC-90009 reaction were screened through genome-wide CRISPR-Cas9, the researchers found that the ILF2 and ILF3 isoglomer complexes were a new brain protein expression regulator.
the ILF2/ILF3 gene can reduce the production of whole-length brain proteins by regulating the selective shearing of CRBN mRNA, resulting in a reduced individual response to CC-90009.
addition, unlike other brain protein regulators, mTOR signals and combined stress responses to CC-90009 also have specific regulatory effects.
TSC1 and TSC2 inactivation inhibit the growth inhibition of CC-90009, thus reducing the CC-90009 induced GSPT1 in combination with CRBN and subsequent degradation of GSPT1, thus avoiding excessive activation of the mTOR path.
, on the other hand, GSPT1 degradation promotes the activation of the AML cell GCN1/GCN2/ATF4 path and subsequent apoptosis.
overall, the activity of CC-90009 is mediated by multiple signaling network paths within AML and LSC, and this study provides ideas for further evaluating the clinical application of CC-90009.
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