The design of transcription factor-based inhibitors to target Myc: drop the Myc!

Ellenbroek, B.D. (2026)

Doctoral Thesis

The master regulator Myc is a DNA-binding protein that can bind DNA when it is in complex with its protein partner Max and is involved in more than 50% of all human cancers. Due to Myc’s intrinsically disordered nature and therefore lack of binding pockets, it is considered an ‘undruggable’ protein using the classical small molecule approach. This thesis describes how proteins and peptides can be designed to inhibit Myc. Through an extensive literature study, inhibition strategies are explained to provide a deeper understanding of peptide-based drug discovery. Additionally, this thesis explores two strategies to inhibit Myc activity: indirect Myc inhibition by blocking its DNA binding site and direct Myc inhibition by disrupting the Myc-Max complex. For indirect Myc inhibition, miniproteins were designed through structure-based design strategies based on the Myc inhibitor Omomyc. One strategy explores replacing parts of Omomyc by chemical linkers, whereas the other strategy locks Omomyc in its active conformation using staples. For direct Myc inhibition AlphaFold-multimer was applied to design a peptide-based inhibitor based on the interaction between Myc and Miz-1. All chapters combined provide an extensive overview on how to inhibit Myc and the possibilities of protein-based drug discovery.

• Myc
• Max
• Structure-based design
• Miniprotein
• Miz-1
• AlphaFold-Multimer
• Transcription factor
• Omomyc

• All authors: Ellenbroek, B.D.
• Supervisor: Eck, M. van; Martin, N.I.
• Co-supervisor: Pomplun, S.J.
• Committee: Heitman, L.H.; Thomas, F.; Jbara, M.; Kros, A.; Lange, E.C.M. de
• Qualification: Doctor (dr.)
• Awarding Institution: Leiden Academic Centre for Drug Research (LACDR), Faculty of Science, Leiden University
• Date: 2026-06-10
• ISBN (print): 9789465374475
• Sponsorship: Horizon 2020(H2020)
• Grant number: 101039354