Evaluation of strategies to target the Myc oncogene

Aim: Myc overexpression or dysregulation is a hallmark of most malignancies, yet targeting of Myc-driven cancers remains a clinically unmet need 1 . Both indirect and direct modalities of Myc inhibition have been evaluated. Indirect Myc targeting via inhibition of its binding to partner proteins is challenging due to issues around redundancy and patient selection. Furthermore, antisense and other epigenetic approaches have so far failed. While direct targeting is challenging due to the intrinsically disordered nature of Myc 2 , peptides/miniproteins, such as OmoMYC 3 (which essentially prevent the interaction of Myc with its obligate heterodimeric binding partner, Max) are being tested in the clinic. It is currently unclear whether a small molecule approach for Myc inhibition will be feasible. Here, we used biophysical, biochemical and functional assays to test published tool compounds that are reported to target Myc. Based on publicly available data, we also present strategies for selection of patients with Myc-driven cancer. Methods: Commercially available Myc targeting compounds were tested in direct Myc:Max binding assays using NMR. OmoMYC was synthesized and purified by Peak Proteins. An HTRF DNA binding assay was developed to investigate functional binding of recombinant Myc:Max complexes to DNA using consensus E-Box or control oligonucleotides. Myc and Max have been overexpressed in HEK293T cell lines to generate cell lysates for biochemical testing. Results : Compounds reported to directly inhibit Myc did not bind to the MYC/MAX heterodimer in our assays. We confirmed the ability of OmoMYC to displace Myc binding to the canonical E-box sequence in biochemical assays and in cell lysates. We also identified biomarkers that are predictive of increased sensitivity to genetic inhibition of Myc, which may facilitate patient selection strategies. Conclusion : Early data from clinical trials with OmoMYC suggest that direct targeting of Myc is feasible. Small molecule inhibition of Myc would offer distinct pharmacological advantages and is, therefore, a first-in-class opportunity. A significant improvement in the affinity of Myc-targeting small molecules will be required to fully validate its potential as an oncology target. References: 1) Whitfield J.R. and Soucek L., MYC in cancer: from undruggable target to clinical trials, Nat. Rev. Drug Disc. (2025)2) Madden S.K. et al., Taking the Myc out of cancer: toward therapeutic strategies to directly inhibit c-Myc, Mol. Can. (2021)3) Demma M.J. et al., Omomyc reveals new mechanisms to inhibit the MYC Oncogene, MCB (2019)