biostudies-literatureSiokatas CEuropean Union and Greek national funds3955-3968https://www.ebi.ac.uk/biostudies/studies/S-EPMC11650737biostudies-literatureUnknown7(12)Although small-molecule inhibitors with moderate efficacy targeting MYC have been previously described, to this point, research efforts have failed to bring a suitable small-molecule MYC inhibitor to the clinic. Herein, the discovery of a series of novel MYC degraders bearing VHL to target the "undruggable" MYC is presented. The molecules are based on connecting a known MYC binder to a VHL ligand or pomalidomide to induce MYC degradation in various cancer cells known to express MYC. Representative compounds from our work induced MYC degradation in a time- and dose-dependent manner. Selected compounds, <b>CSI86</b> and <b>CSI107</b>, displayed antiproliferative activity (IC₅₀ values of 13-18 μM) against breast and prostate cancer cells. The lead molecules were further evaluated iACS pharmacology & translational scienceDeveloping MYC Degraders Bearing the Von Hippel-Lindau Ligand to Target the "Undruggable" MYC.PMC11650737MIS 5028091MIS5002691MIS 5002550Lampropoulou AKontostathi MTamvakopoulos CSmina ASarli VPolitou ASSoupsana KKarra AVChristoforidis SKarampelas TSiokatas CfalseDeveloping MYC Degraders Bearing the Von Hippel-Lindau Ligand to Target the "Undruggable" MYC.Although small-molecule inhibitors with moderate efficacy targeting MYC have been previously described, to this point, research efforts have failed to bring a suitable small-molecule MYC inhibitor to the clinic. Herein, the discovery of a series of novel MYC degraders bearing VHL to target the "undruggable" MYC is presented. The molecules are based on connecting a known MYC binder to a VHL ligand or pomalidomide to induce MYC degradation in various cancer cells known to express MYC. Representative compounds from our work induced MYC degradation in a time- and dose-dependent manner. Selected compounds, <b>CSI86</b> and <b>CSI107</b>, displayed antiproliferative activity (IC₅₀ values of 13-18 μM) against breast and prostate cancer cells. The lead molecules were further evaluated i2024-01-01T00:00:00Z2024 Dec2026-06-06T13:24:07.999Z2026-05-31T03:07:27.315ZS-EPMC116507373969827010.1021/acsptsci.4c00452