Abstract LB193: Developing protein degraders to target the “undruggable” MYC

Abstract Despite significant progress in cancer treatment, certain cancers remain difficult to target, particularly when aberrant expression of the c-MYC protein is involved, a target considered "undruggable" due to its disordered structure and lack of binding sites. Efforts to generate small molecule MYC inhibitors (Stellas et al 2014, Truica et al 2021) have been remarkable but have not yet resulted into MYC inhibitors available to the clinician. A promising alternative approach to targeting c-MYC and other “undruggable” targets is the discovery of PROteolysis-TArgeting Chimeras (PROTACs), heterobifunctional molecules that recruit E3 ubiquitin ligases to degrade specific proteins through the cell’s natural proteolysis mechanisms. Recent studies by our group (Siokatas et al 2024) showed that selected MYC degraders exhibited antiproliferative activity against prostate and breast cancer cells (IC50 values 10-20 μM), and induced MYC degradation in a dose-dependent manner (DC50 ∼ 10 μM). The degradation mechanism was shown to be proteasome-mediated, as degradation was rescued by the proteasomal inhibitor MG-132. Further, a negative control (epimer of the lead degrader) was synthesized to confirm that degradation by our lead PROTAC occurs via E3 ligase-mediated ubiquitination. Our work was expanded to quantify PROTACs in biological fluids using Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) assays and was applied to cell uptake studies that revealed that selected leads have significant permeability (∼ 20% uptake), and blood exposure in mice following administration. The proof of concept study by Siokatas et al is extremely promising and highlights the vast opportunities that exist with MYC degradation as a potential strategy for anticancer therapy. More specifically our work presented herein expands on our previous research with mechanism of action studies that address the time-dependent effects of our lead degraders and their applicability to challenging cancers such as triple-negative breast cancer (TNBC). As cell permeability is often a limitation of PROTAC efficacy, comparison between various leads was performed to provide correlations between cell permeability and efficacy in a triple negative cancer cell line. At this stage, we are advancing our research by developing molecular glue MYC degraders with reduced molecular weights (reducing molecular weight from approximately 1200 to 750 g/mol) in order to improve their drug-like properties. Preliminary results indicate that these molecules are highly effective in promoting MYC degradation (60% relative MYC expression after incubation with molecular glue at 10 μM for 24h) and in inhibiting cellular proliferation (IC50 values at 10 μM). We anticipate that our findings will contribute to therapeutic approaches to cancer, and to more targeted and effective therapies. (1) Stellas D, et al. "Therapeutic effects of an anti-Myc drug on mouse pancreatic cancer." Journal of the National Cancer Institute 106.12 (2014): dju320. (2) Truica M, et al. "Turning up the heat on MYC: progress in small-molecule inhibitors." Cancer research 81.2 (2021): 248-253. (3) Siokatas C, et al. "Developing MYC Degraders Bearing the Von Hippel-Lindau Ligand to Target the “Undruggable” MYC." ACS Pharmacology & Translational Science 7.12 (2024): 3955-3968. Citation Format: Alexandra Lampropoulou, Christos Siokatas, Nikolaos Plakas, Aikaterini-Maria Petrova, Vasiliki Sarli, Constantin Tamvakopoulos. Developing protein degraders to target the “undruggable” MYC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB193.