Unleashing CC-90009: Targeting GSPT1 for Acute Myeloid Leukemia Elimination

The research abstract describes the development of a novel cereblon E3 ligase modulator (CELMoD), CC-90009, designed to selectively target the translation termination factor GSPT1 for degradation via the CRL4CRBN E3 ubiquitin ligase complex. This approach has shown significant growth inhibition in AML cell lines and patient samples, with minimal off-target effects compared to previous CELMoDs like CC-885.

Through cell-based phenotypic screening of 11 human AML cell lines with common oncogenic mutations, CC-90009 was identified as a potent agent with an IC50 ranging from 3 to 75 nM. The compound induced rapid and efficient leukemic cell death, eliminating over 82% of leukemic cells within 24 hours and nearly all within 96 hours, while showing modest activity against normal lymphocytes.

The anti-AML activity of CC-90009 was found to be CRBN-dependent, as CRISPR/Cas9-mediated knockout of CRBN abrogated its effects. Mass spectrometry analysis confirmed the selective reduction of GSPT1 abundance in treated AML cells, with proteasomal inhibition or CRL4CRBN inactivation blocking this degradation. Overexpression of a GSPT1-resistant mutant rendered cells resistant to CC-90009, while partial knockdown of GSPT1 enhanced the compound's response.

Mechanistically, GSPT1 degradation by CC-90009 activates the integrated stress response pathway, leading to apoptosis induction and proliferation inhibition. As a first-in-class GSPT1 degrader, CC-90009's clinical development is supported by its profound antiproliferative activity in over 80% of human AML cell lines and patient blasts, underscoring the rationale for its ongoing phase 1 study in relapsed or refractory AML patients (NCT02848001).

The disclosures section notes affiliations and potential conflicts of interest involving Celgene Corporation and Global Blood Therapeutics (GBT) for several individuals involved in the study.