The Cereblon Modulator CC-885 Exhibits Antitumor Activity

Immunomodulatory drugs including lenalidomide have proven beneficial in treating patients with multiple myeloma and 5q-deletion–associated myelodysplastic syndrome. These drugs bind to cereblon (CRBN) and promote the recruitment, ubiquitination, and degradation of substrate proteins mediated by the CRL4^CRBN E3 ubiquitin ligase. Several CRL4^CRBN substrates have been identified, including transcription factors Ikaros and Aiolos, and CK1α. No clear sequence or structural homology predicts susceptibility to immunomodulatory drugs, prompting Matyskiela, Lu, Ito, and colleagues to investigate the mechanisms of substrate binding to cereblon, as degradation of unidentified targets could result in antitumor activity. A screen of cereblon ligand analogues identified CC-885 as a compound that inhibited the growth of a broad spectrum of tumor cell lines and patient-derived acute myeloid leukemia (AML) cells. CC-885 shares a glutarimide ring with lenalidomide and its analogs, which interacts with cereblon. Deletion of cereblon abolished the antiproliferative effects of CC-885, indicating that the effects on proliferation are cereblon-dependent. CC-885 mediated binding of the translation termination factor GSPT1 to CRL4^CRBN, enhanced the interaction between cereblon and GSPT1, and promoted GSPT1 degradation; however, other immunomodulatory drugs did not, indicating that CC-885 specifically induced GSPT1 degradation. Further, the cytotoxic effects of CC-885 were largely due to depletion of GSPT1. The crystal structure of cereblon bound to the adaptor protein DDB1, CC-885, and GSPT1 was solved. The structure showed direct interactions of GSPT1 with both cereblon and CC-885 at a “hotspot” on the cereblon surface, and revealed that cereblon was essential for the complex formation. Degrons are motifs that direct E3 ligase interactions, and a structural GSPT1 degron was identified, rather than a primary peptide sequence. Ikaros binds cereblon through a similar structural feature, suggesting a common mechanism for substrate recruitment. These findings identify a structural degron that may occur in numerous substrates and could be targeted for degradation by cereblon modulators, such as CC-885, to promote antitumor activity.

Matyskiela ME, Lu G, Ito T, Pagarigan B, Lu CC, Miller K, et al. A novel cereblon modulator recruits GSPT1 to the CRL4^CRBN ubiquitin ligase. Nature 2016 Jun 22 [Epub ahead of print].