G protein-coupled receptor class C group 5 member D and cereblon E3 ligase complex (GPRC5D-CRBN complex)

The GPRC5D and cereblon E3 ligase complex is a therapeutic target assembly involved in the treatment of multiple myeloma. GPRC5D is a seven-transmembrane orphan receptor uniquely overexpressed on the surface of malignant plasma cells, while cereblon (CRBN) serves as the substrate receptor for the CRL4 E3 ubiquitin ligase complex. In the context of targeted protein degradation, bifunctional molecules or molecular glues facilitate the formation of this ternary complex, bringing the E3 ligase into close proximity with GPRC5D to trigger its ubiquitination and subsequent destruction by the 26S proteasome. This approach aims to eliminate myeloma cells by depleting a critical surface antigen and disrupting survival signaling. Additionally, the interaction between GPRC5D-targeted therapies and cereblon modulators is utilized to enhance T-cell activation and overcome drug resistance in relapsed or refractory disease settings.

Other names

GPRC5D/CRBN complexGPRC5D-Cereblon complexGPRC5D-CRL4-CRBN ternary complex

Targeted protein degradation via recruitment of the CRL4-CRBN E3 ligase to GPRC5D, leading to ubiquitination and proteasomal degradation of the receptor; or synergistic enhancement of T-cell mediated cytotoxicity through cereblon modulation.