Tom & Conner's review on Targeting Epigenetic Modulators Using PROTAC Degraders is now published in BMCL

  • Graphical Abstract
  • Figure 1. Current FDA approved inhibitor-based therapies for disease-causing epigenetic proteins.
  • Figure 2. Challenges faced in the development of small-molecule inhibitors for epigenetic modulators.
  • Figure 3. (A) Cartoon representation of the differing mechanism of action between small molecule inhibitors (occupancy-based pharmacology) and PROTAC degraders. (B) Cartoon showing the potential mechanisms by which PROTACs can degrade or destabilise target proteins as well as other associated subunits in multi-subunit complexes.
  • Figure 4. Structure of a PROTAC degrader, with POI ligand shown in pink, linker shown in black, and E3 ligase ligand shown in blue. The chemical structures of all PROTACs targeting epigenetic disease-causing proteins mentioned herein are included.

Great review article by Tom and Conner  

Read the full article here.

Read the article open access before April 29, 2022 via the personalized Share Link here


Authors: Thomas Webb, Conner Craigon, Alessio Ciulli*

Title: Targeting Epigenetic Modulators Using PROTAC Degraders: Current Status and Future Perspective


Epigenetic modulators perform critical functions in gene expression for rapid adaption to external stimuli and are prevalent in all higher-order organisms. The establishment of a link between dysregulation of epigenetic processes and disease pathogenesis, particularly in cancer, has led to much interest in identifying drug targets. This prompted the development of small molecule inhibitors, primarily in haematological malignancies. While there have been epigenetic-targeting drugs to receive FDA approval for the treatment of cancers, many suffer from limited applicability, toxicity and the onset of drug resistance, as our understanding of the biology remains incomplete. The recent advent of genome-wide RNAi and CRISPR screens has shed new light on loss of specific proteins causing vulnerabilities of specific cancer types, highlighting the potential for exploiting synthetic lethality as a therapeutic approach. However, small molecule inhibitors have largely been unable to recapitulate phenotypic effects observed using genome-wide knockdown approaches. This mechanistic disconnect and gap are set to be addressed by targeted protein degradation. Degraders such as PROTACs targeting epigenetic proteins recapitulate CRISPR mediated genetic knockdown at the post-translational level and therefore can better exploit the target druggability. Here, we review the current landscape of epigenetic drug discovery, the rationale behind and progress made in the development of PROTAC degraders and look at future perspectives for the field.