Abstract SY37-02: Ligand-directed degradation of GSPT1 by a novel cereblon modulator drives potent antitumor effects

The protein cereblon is part of the CRL4-CRBN E3 ubiquitin ligase complex, and has been shown to be the molecular target for the drugs lenalidomide and pomalidomide. These drugs bind to the surface of cereblon, triggering the recruitment of substrate proteins to the ligase complex where they can be ubiquitinated and subsequently degraded by the proteosome. By this mechanism, lenalidomide and pomalidomide cause the degradation of the zinc finger transcription factors Ikaros and Aiolos, which mediate the antimyeloma activity of these compounds. Here we describe the discovery of CC-885, a novel cereblon modulator with potent and broad-spectrum antiproliferative activity against a panel of tumor cell lines. Acute myeloid leukemia (AML) cell lines and patient-derived AML cells show particular sensitivity to CC-885 treatment. CC-885 achieves this activity by causing the degradation of G1 to S phase transition 1 (GSPT1), a translation termination factor required for the release of nascent peptides from the ribosome. A crystal structure of cereblon in complex with the ligase adapter protein DDB1, as well as CC-885 and GSPT1, reveals that GSPT1 interacts with both CC-885 and the surface of cereblon. The principal molecular feature on GSPT1 that binds to cereblon is a beta-hairpin incorporating a glycine residue that docks against CC-885. Surprisingly, we found evidence that a similar molecular feature mediates Ikaros recruitment, even though there is no common structural fold or sequence homology other than the key glycine residue. We thereby define the common molecular feature, or degron, shared by the known cereblon neomorphic substrates. We further describe a novel therapeutic target, GSPT1, with promise in cancer such as AML. These results further show that cereblon-mediated protein degradation can be directed against new proteins and that this mechanism enables the targeting of multiple protein classes that may be considered undruggable with conventional approaches. Citation Format: Mary Matyskiela, Gang Lu, Takumi Ito, Barbra Pagarigan, Chin-Chu Lu, Karen Miller, Wei Fang, Nai-Yu Wang, Derek Nguyen, Jack Houston, Gilles Carmel, Tam Tran, Mariko Riley, Lyn9Al Nosaka, Gabriel Lander, Svetlana Gaidarova, Shuichan Xu, Alexander Ruchelman, Hiroshi Handa, James Carmichale, Thomas O. Daniel, Brian E. Cathers, Antonia Lopez-Girona, Philip Chamberlain. Ligand-directed degradation of GSPT1 by a novel cereblon modulator drives potent antitumor effects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY37-02. doi:10.1158/1538-7445.AM2017-SY37-02