# Insights into the Design of MYC-Targeting Proteolysis Targeting Chimeras (PROTACs)

## TL;DR

This study explores the design of PROTACs to target the MYC protein in cancer, but finds that the compounds are ineffective at degrading MYC in cells.

## Contribution

The paper presents the synthesis and testing of novel MYC-targeted PROTACs and identifies challenges in targeting intrinsically disordered proteins.

## Key findings

- Synthesized MYC-targeted PROTACs showed only moderate effects on cell viability.
- None of the PROTACs induced detectable MYC degradation at relevant concentrations.
- Rapid degradation of PROTACs in microsomes may explain their cellular inactivity.

## Abstract

The oncogenic transcription factor MYC is a key driver of the development and progression of various types of cancer, but its intrinsically disordered structure and dependence on protein–protein interactions make it a difficult therapeutic target. Proteolysis-targeting chimeras (PROTACs) are bifunctional molecules that can induce the selective degradation of disease-relevant proteins. In this study, we report the synthesis and biological testing of a series of novel MYC-targeted PROTACs derived from the MYC inhibitor EN4. These ligands were conjugated to cereblon (CRBN) or von Hippel–Lindau (VHL) E3 ligase recruiters using different linker architectures and connection sites. The resulting PROTACs were synthesized in high purity and characterized analytically. Cellular evaluation in HEK293T, Panc-1 and HCT-116 cancer cells revealed only moderate reductions in cell viability. Unfortunately, none of the synthesized PROTACs showed detectable MYC degradation at biologically relevant concentrations. Testing the stability of the PROTACs in microsomes showed rapid degradation, which may be a reason for the observed inactivity in cells. These results underscore the significant challenges associated with the targeted protein degradation of intrinsically disordered transcription factors such as MYC. Further studies are necessary to identify additional causes for the lack of MYC degradation and to optimize the chemical structures accordingly.