A novel Cereblon E3 ligase modulator with antitumor activity in gastrointestinal cancer
Svenja Lier, Andreas Sellmer, Felix Orben, Stephanie Heinzlmeir, Lukas Krauß, Christian Schneeweis, Zonera Hassan, Carolin Schneider, Arlett Schäfer, Herwig Pongratz, Thomas Engleitner, Rupert Öllinger, Anna Kuisl, Florian Bassermann, Christoph Schlag, Bo Kong, Stefan Dove, Bernhard Küster, Roland Rad, Maximilian Reichert, Matthias Wirth, Dieter Saur, Siavosh Mahboobi, Günter Schneider
Abstract
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.