The Action Mechanism of the Myc Inhibitor Termed Omomyc May Give Clues on How to Target Myc for Cancer Therapy

Abstract

Recent evidence points to Myc – a multifaceted bHLHZip transcription factor deregulated in the majority of human cancers – as a priority target for therapy. How to target Myc is less clear, given its involvement in a variety of key functions in healthy cells. Here we report on the action mechanism of the Myc interfering molecule termed Omomyc, which demonstrated astounding therapeutic efficacy in transgenic mouse cancer models in vivo. Omomyc action is different from the one that can be obtained by gene knockout or RNA interference, approaches designed to block all functions of a gene product. This molecule – instead – appears to cause an edge-specific perturbation that destroys some protein interactions of the Myc node and keeps others intact, with the result of reshaping the Myc transcriptome. Omomyc selectively targets Myc protein interactions: it binds c- and N-Myc, Max and Miz-1, but does not bind Mad or select HLH proteins. Specifically, it prevents Myc binding to promoter E-boxes and transactivation of target genes while retaining Miz-1 dependent binding to promoters and transrepression. This is accompanied by broad epigenetic changes such as decreased acetylation and increased methylation at H3 lysine 9. In the presence of Omomyc, the Myc interactome is channeled to repression and its activity appears to switch from a pro-oncogenic to a tumor suppressive one. Given the extraordinary therapeutic impact of Omomyc in animal models, these data suggest that successfully targeting Myc for cancer therapy might require a similar twofold action, in order to prevent Myc/Max binding to E-boxes and, at the same time, keep repressing genes that would be repressed by Myc.

Inhibitor of MYC identified in a Kröhnke pyridine library

“…The data on the xenotransplant of a MYC-dependent human cancer cell line show a block of tumor growth in the presence of the compound. However, the effects of KJ-Pyr-9 in cell culture and in vivo are cytostatic, not cytocidal, in contrast to the effect of Omomyc overexpression in tumors (49). This may stem from incomplete inhibition of MYC, with residual activity facilitating cell survival, or it may reflect fundamental differences between Omomyc and KJ-Pyr-9 as inhibitors of MYC.…”

The Role of MIZ-1 in MYC-Dependent Tumorigenesis

“…Recent data suggest that the OmoMyc-dominant-negative allele of MYC differentially affects MYC/ MAX and MYC/MIZ-1 complexes (Soucek et al 2008;Savino et al 2011). If these can be extended to human tumors, proof-of-principle experiments will be possible that allow us to decipher the contribution of MYC/MIZ-1 complexes to MYC-dependent transformation of human tumors.…”

A critical role for Mnt in Myc-driven T-cell proliferation and oncogenesis

“…c-Myc (hereafter, Myc) promotes proliferation by coordinating a variety of cellular processes, including those promoting nutrient uptake and metabolism, ribosome biogenesis and translation, mitochondria biogenesis, and cell cycle progression (3)(4)(5). The broad program of gene expression and cellular processes governed by Myc can make cancer cells highly dependent on its continued activities, and downregulating or inactivating Myc can suppress tumor growth (2,6,7).…”