6XK9

Cereblon in complex with DDB1, CC-90009, and GSPT1

Summary for 6XK9

• Entry DOI: 10.2210/pdb6xk9/pdb
• Descriptor: Eukaryotic peptide chain release factor GTP-binding subunit ERF3A, DNA damage-binding protein 1, Protein cereblon, ... (5 entities in total)
• Functional Keywords: ddb1, molecular glue, degradation, cc-90009, acute myeloid leukemia, ligase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 392434.18

Authors

Clayton, T.L.,Tran, E.T.,Zhu, J.,Pagarigan, B.E.,Matyskiela, M.E.,Chamberlain, P.P. (deposition date: 2020-06-25, release date: 2020-12-02, Last modification date: 2023-10-18)

Primary citation

Surka, C.,Jin, L.,Mbong, N.,Lu, C.C.,Jang, I.S.,Rychak, E.,Mendy, D.,Clayton, T.,Tindall, E.,Hsu, C.,Fontanillo, C.,Tran, E.,Contreras, A.,Ng, S.W.K.,Matyskiela, M.,Wang, K.,Chamberlain, P.,Cathers, B.,Carmichael, J.,Hansen, J.,Wang, J.C.Y.,Minden, M.D.,Fan, J.,Pierce, D.W.,Pourdehnad, M.,Rolfe, M.,Lopez-Girona, A.,Dick, J.E.,Lu, G.
CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells.
Blood, 137:661-677, 2021

PubMed 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).

PubMed: 33197925
DOI: 10.1182/blood.2020008676

Experimental method

X-RAY DIFFRACTION (3.64 Å)