Protein degradation agents based on the ubiquitin-proteasome pathway include a part of molecular glues. A molecular glue is a small molecule that stabilizes the interaction between two proteins that do not normally interact. If one of the proteins is ubiquitin ligase, molecular glue can cause another protein to undergo ubiquitin modification and degradation through the proteasome pathway, which is similar to PROTAC. The most commonly employed molecular glue induces a novel interaction between a substrate receptor of an E3 ubiquitin ligase and a target protein leading to proteolysis of the target. Examples of molecular glues that induce degradation of protein targets include the immunomodulatory imide drug (also known as IMiD; e.g., Lenalidomide). IMiDs act as molecular glue as small molecules that are capable of converting a target protein into a new substrate (neosubstrate) targetable by the E3 ubiquitin ligase CRL4CRBN.
Golcadomide (CC-99282) is a potent and orally active CRBN E3 ligase modulator (CELMoD; or molecular glue) with immunomodulating and antineoplastic activities.
Specifically, Golcadomide works with CRBN to induce potent and targeted degradation of Ikaros and Aiolos. Moreover, Golcadomide induces the secretion of IL-2 and effector cytokines and chemokines (GM-CSF, IFNγ, and TNFα) that correlated with Ikaros and Aiolos degradation. Especially, Golcadomide exhibits stronger antiproliferative, apoptotic, and immunostimulatory activities compared with Lenalidomide and other CELMoD agents. For example, in various diffuse large B-cell lymphoma (DLBCL) cells, Golcadomide shows enhanced antiproliferative and proapoptotic activities compared with Lenalidomide. In addition, Golcadomide induces activation of caspases and cleavage of PARP1 and decreases the levels of the important oncogenic factors c-myc and IRF4. Furthermore, in a xenograft model, the combination of Golcadomide and Rituximab achieved complete tumor regression. Therefore, Golcadomide has the potential for research of the non-Hodgkin lymphomas.
To sum up, Golcadomide is a potent and orally active CRBN E3 ligase modulator with immunomodulating and antineoplastic activities.
References:
[1] Julio C Chavez, et al. Clin Lymphoma Myeloma Leuk. 2022 Oct;22 Suppl 2:S377-S378.
[2] Ota Fuchs, et al. Blood Rev. 2022 Jul 31;100994.