Cereblon modulator CC-885 induces CRBN-dependent ubiquitination and degradation of CDK4 in multiple myeloma

Abstract

Molecular glue degraders that hijack cellular E3 ubiquitin ligases to target disease-driven proteins for proteosome-dependent degradation are emerging as a promising treatment. Immunomodulatory drugs are classical molecular glue that bind to cereblon (CRBN) to repurpose the function of the CRL4(CRBN) E3 ubiquitin ligase and developed to treat various hematological malignancies. Recently, a novel cereblon modulator CC-885 was developed to elicit broad antitumor activity. Although the degradation of GSPT1 is essential for the broad in vitro antitumor activity of CC-885, it is unclear whether other neosubstrates also contribute to the pharmacological effects of CC-885, especially in multiple myeloma (MM). Here, we show that CC-885 treatment caused growth retardant of MM cells via impairment of cell cycle progression and cell death both in vitro and in vivo. Mechanically, CC-885 selectively induced the ubiquitination and degradation of CDK4 in MM cells in a CRBN-dependent manner. CC-885-mediated CDK4 destruction decreased the phosphorylation of the tumor suppressor retinoblastoma (RB) and prevented the expression of E2F downstream genes. Importantly, genetic ablation or pharmacological inhibition of CDK4 enhances CC-885-induced cytotoxicity in MM cells, suggesting CDK4 destruction contributed to the cytotoxicity of CC-885 in MM cells.

Keywords: CC-885; CDK4; CRBN; E3 ubiquitin ligase; Multiple myeloma.