Drugging the "Undruggable" MYCN Oncogenic Transcription Factor: Overcoming Previous Obstacles to Impact Childhood Cancers

Abstract

Effective treatment of pediatric solid tumors has been hampered by the predominance of currently "undruggable" driver transcription factors. Improving outcomes while decreasing the toxicity of treatment necessitates the development of novel agents that can directly inhibit or degrade these elusive targets. MYCN in pediatric neural-derived tumors, including neuroblastoma and medulloblastoma, is a paradigmatic example of this problem. Attempts to directly and specifically target MYCN have failed due to its similarity to MYC, the unstructured nature of MYC family proteins in their monomeric form, the lack of an understanding of MYCN-interacting proteins and ability to test their relevance in vivo, the inability to obtain structural information on MYCN protein complexes, and the challenges of using traditional small molecules to inhibit protein-protein or protein-DNA interactions. However, there is now promise for directly targeting MYCN based on scientific and technological advances on all of these fronts. Here, we discuss prior challenges and the reasons for renewed optimism in directly targeting this "undruggable" transcription factor, which we hope will lead to improved outcomes for patients with pediatric cancer and create a framework for targeting driver oncoproteins regulating gene transcription.

Figure 1:. Highlighted challenges and technologic advances in identification and validation of a direct MYCN targeting compound.

Biochemically-derived MYCN interactomes have recently revealed a large number of potential complexes to target and are contrasted to MYC interactomes (not shown). Which complexes are essential to tumor maintenance can now be identified using genetic loss-of-function testing in appropriate in vivo models (e.g. neural epithelial stem [NES] cell and patient-derived xenograft [PDX] models). Once oncogenic complexes are identified, these can be purified and used in structural studies, aided by advancements in cryo-EM technology. Challenges to the identification of small molecule inhibitors can be addressed by using a bind and degrade approach. DEL screens can facilitate the identification of binders unique to MYCN complexes as compared to MYC complexes. These compounds can then be linked to E3 ligase ligands to create proteolysis-targeting chimeras (PROTACs), optimized using structure as a guide, and tested in cell line and mouse models to confirm degradation, ensure anti-tumor activity, and determine selectivity. Once active and selective PROTACs are identified, they can be prioritized for IND-enabling studies and eventual clinical testing. Interactome modified from http://pennlab.ca/research/#, protein structure from the PDB (https://www.rcsb.org/structure/5G1X), and drawing tools from motifolio.com.