CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells

  • Blood. 2021 Feb 4;137(5):661-677. doi: 10.1182/blood.2020008676.
Christine Surka  1 ,  Liqing Jin  2 ,  Nathan Mbong  2 ,  Chin-Chun Lu  1 ,  In Sock Jang  1 ,  Emily Rychak  1 ,  Derek Mendy  1 ,  Thomas Clayton  1 ,  Elizabeth Tindall  1 ,  Christy Hsu  1 ,  Celia Fontanillo  1 ,  Eileen Tran  1 ,  Adrian Contreras  1 ,  Stanley W K Ng  2 ,  Mary Matyskiela  1 ,  Kai Wang  1 ,  Philip Chamberlain  1 ,  Brian Cathers  1 ,  James Carmichael  1 ,  Joshua Hansen  1 ,  Jean C Y Wang  2  3  4 ,  Mark D Minden  2  3  4 ,  Jinhong Fan  5 ,  Daniel W Pierce  5 ,  Michael Pourdehnad  5 ,  Mark Rolfe  1 ,  Antonia Lopez-Girona  1 ,  John E Dick  2  6 ,  Gang Lu  1
Affiliations
  • 1. Bristol-Myers Squibb, San Diego, CA.
  • 2. Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • 3. Department of Medicine, University of Toronto, Toronto, ON, Canada.
  • 4. Division of Medical Oncology and Hematology, University Health Network, Toronto, ON, Canada.
  • 5. Bristol-Myers Squibb, San Francisco, CA; and.
  • 6. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
PMID: 33197925 DOI: 10.1182/blood.2020008676
Abstract

A number of clinically validated drugs have been developed by repurposing the CUL4-DDB1-CRBN-RBX1 (CRL4CRBN) E3 ubiquitin Ligase complex with molecular glue degraders to eliminate disease-driving proteins. Here, we present the identification of a first-in-class GSPT1-selective Cereblon E3 Ligase modulator, CC-90009. Biochemical, structural, and molecular characterization demonstrates that CC-90009 coopts the CRL4CRBN to selectively target GSPT1 for ubiquitination and proteasomal degradation. Depletion of GSPT1 by CC-90009 rapidly induces acute myeloid leukemia (AML) Apoptosis, reducing leukemia engraftment and leukemia stem cells (LSCs) in large-scale primary patient xenografting of 35 independent AML samples, including those with adverse risk features. Using a genome-wide CRISPR-Cas9 screen for effectors of CC-90009 response, we uncovered the ILF2 and ILF3 heterodimeric complex as a novel regulator of Cereblon expression. Knockout of ILF2/ILF3 decreases the production of full-length Cereblon protein via modulating CRBN messenger RNA alternative splicing, leading to diminished response to CC-90009. The screen also revealed that the mTOR signaling and the integrated stress response specifically regulate the response to CC-90009 in contrast to other Cereblon modulators. Hyperactivation of the mTOR pathway by inactivation of TSC1 and TSC2 protected against the growth inhibitory effect of CC-90009 by reducing CC-90009-induced binding of GSPT1 to Cereblon and subsequent GSPT1 degradation. On the Other hand, GSPT1 degradation promoted the activation of the GCN1/GCN2/ATF4 pathway and subsequent Apoptosis in AML cells. Collectively, CC-90009 activity is mediated by multiple layers of signaling networks and pathways within AML blasts and LSCs, whose elucidation gives insight into further assessment of CC-90009s clinical utility. These trials were registered at www.clinicaltrials.gov as #NCT02848001 and #NCT04336982).

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