A novel Cereblon E3 ligase modulator with antitumor activity in gastrointestinal cancer

Targeted protein degradation offers new opportunities to inactivate cancer drivers and has successfully entered the clinic. Ways to induce selective protein degradation include proteolysis targeting chimera (PROTAC) technology and immunomodulatory (IMiDs) / next-generation Cereblon (CRBN) E3 ligase modulating drugs (CELMoDs). Here, we aimed to develop a MYC PROTAC based on the MYC-MAX dimerization inhibitor 10058-F4 derivative 28RH and Thalidomide, called MDEG-541. We show that a subgroup of gastrointestinal cancer cell lines and primary patient-derived organoids are MDEG-541 sensitive. Although MYC expression was regulated in a CRBN-, proteasome-and ubiquitin-dependent manner, we provide evidence that MDEG-541 induced the degradation of CRBN neosubstrates, including G1 to S phase transition 1/2 (GSPT1/2) and the Polo-like kinase 1 (PLK1). In sum, we have established a CRBN-dependent degrader of relevant cancer targets with activity in gastrointestinal cancers.

Automated summary

Targeted protein degradation is a promising approach for inactivating cancer drivers, and it has been successfully applied in clinical settings. This study focused on developing a MYC PROTAC called MDEG-541, based on the MYC-MAX dimerization inhibitor 10058-F4 derivative 28RH and Thalidomide. The results showed that MDEG-541 could selectively degrade CRBN neosubstrates, including GSPT1/2 and PLK1, and exhibited activity in gastrointestinal cancers.