Developing MYC Degraders Bearing the Von Hippel-Lindau Ligand to Target the "Undruggable" MYC.

Abstract

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, CSI86 and CSI107, displayed antiproliferative activity (IC₅₀ values of 13-18 μM) against breast and prostate cancer cells. The lead molecules were further evaluated in terms of cell uptake, potential to degrade MYC, and pharmacokinetics in mice. Encouraging results presented herein suggest that the presented analogs may serve as prototype structures of future therapeutic agents for the treatment of MYC-dependent tumors. MYC protein degraders can well complement the more established inhibition approaches that have been presented in the past (e.g., disruption of the MYC-MAX complex formation by small-molecule inhibitors).