Omomyc Reveals New Mechanisms To Inhibit the MYC Oncogene

Demma, Mark; Mapelli, Claudio; Sun, Angie; Bodea, Smaranda; Ruprecht, Benjamin; Javaid, Sarah; Wiswell, Derek; Muise, Eric S.; Chen, Shiying; Zelina, John; Orvieto, Federica; Santoprete, Alessia; Altezza, Simona; Tucci, Federica; Escandón, Enrique; Hall, Brian E.; Ray, Kallol; Walji, Abbas M.; O’Neil, Jennifer

doi:10.1128/mcb.00248-19

Cited by 63 publications

(77 citation statements)

References 50 publications

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“…By RNA-seq of colon carcinoma HCT116 cells treated with the Omomyc mini-protein, the authors confirmed the downregulation of Myc-driven gene signatures along with changes in the overall transcription profile. The downregulation of specific Myc targets such as ASNS, SAT1, ID3, and EGR2, as well as CD274-the gene encoding Programed death-ligand 1 (PD-L1)-was also verified by qPCR [82]. In the same study and in line with our own results, CoIP and proximity ligation assay showed that the Omomyc mini-protein forms homodimers and heterodimers with MYC and with MAX, and strongly reduces MYC/MAX dimers.…”

Section: The Omomyc Mini-protein Behaves As Its Transgenically-expressupporting

confidence: 81%

“…In the same study and in line with our own results, CoIP and proximity ligation assay showed that the Omomyc mini-protein forms homodimers and heterodimers with MYC and with MAX, and strongly reduces MYC/MAX dimers. Omomyc/MYC dimers are present in the cytoplasm, while Omomyc/MAX and Omomyc/Omomyc are present also in the nucleus, reinforcing the notion that Omomyc sequesters Myc away from the DNA and binds E-boxes together with MAX or as a homodimer [82]. By E-box DNA binding pulldown coupled with mass spectrometry in lysates from Omomyc-treated Ramos cells, the same authors also confirmed that Omomyc effectively competes with MYC and MAX for DNA binding, but also with other PMN members MXI1, MGA, and MXD3, and with Myc cofactors WDR5 and KMT2A.…”

Section: The Omomyc Mini-protein Behaves As Its Transgenically-expresmentioning

confidence: 54%

“…Most of these data in cancer cells were confirmed in an independent study by Demma et al, who showed that recombinant and chemically synthesized Omomyc penetrated cells through an ATP-dependent mechanism, localized in their nuclei (in particular in the nucleoli) and showed in vitro efficacy in lymphoma and colon cancer cells with deregulated Myc. These cells responded with 50% inhibitory concentrations (IC50s) in the nanomolar or low micromolar range, while lymphoma cells with low Myc responded only at higher peptide concentrations [82]. By RNA-seq of colon carcinoma HCT116 cells treated with the Omomyc mini-protein, the authors confirmed the downregulation of Myc-driven gene signatures along with changes in the overall transcription profile.…”

Section: The Omomyc Mini-protein Behaves As Its Transgenically-expresmentioning

confidence: 86%

“…The authors suggest that Omomyc, unlike Myc, binds high and low affinity promoters with the same affinity, blunting the ability of Myc/MAX to bind and promote transcription from these sites. ReChIP assays in HCT116 cells showed that both Omomyc/MAX and Omomyc/Omomyc dimers were bound to chromatin [82].…”

Section: The Omomyc Mini-protein Behaves As Its Transgenically-expresmentioning

confidence: 99%

“…In the absence of Omomyc, MYC and MAX associate with translating ribosomes, but when Omomyc is present, the MYC ribosomal association is inhibited. Second, MYC is degraded through ubiquitination upon treatment with the Omomyc mini-protein [82].…”

Section: The Omomyc Mini-protein Behaves As Its Transgenically-expresmentioning

confidence: 99%

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Blocking Myc to Treat Cancer: Reflecting on Two Decades of Omomyc

Massó-Vallés

Soucek

2020

Cells

108

109

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First designed and published in 1998 as a laboratory tool to study Myc perturbation, Omomyc has come a long way in the past 22 years. This dominant negative has contributed to our understanding of Myc biology when expressed, first, in normal and cancer cells, and later in genetically-engineered mice, and has shown remarkable anti-cancer properties in a wide range of tumor types. The recently described therapeutic effect of purified Omomyc mini-protein-following the surprising discovery of its cell-penetrating capacity-constitutes a paradigm shift. Now, much more than a proof of concept, the most characterized Myc inhibitor to date is advancing in its drug development pipeline, pushing Myc inhibition into the clinic.

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Section: The Omomyc Mini-protein Behaves As Its Transgenically-expressupporting

confidence: 81%

Section: The Omomyc Mini-protein Behaves As Its Transgenically-expresmentioning

confidence: 54%

Section: The Omomyc Mini-protein Behaves As Its Transgenically-expresmentioning

confidence: 86%

Section: The Omomyc Mini-protein Behaves As Its Transgenically-expresmentioning

confidence: 99%

Section: The Omomyc Mini-protein Behaves As Its Transgenically-expresmentioning

confidence: 99%

See 3 more Smart Citations

Blocking Myc to Treat Cancer: Reflecting on Two Decades of Omomyc

Massó-Vallés

Soucek

2020

Cells

108

109

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Inhibition of Myc transcriptional activity by a mini‐protein based upon Mxd1

et al. 2020

Self Cite

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Myc, a transcription factor with oncogenic activity, is upregulated by amplification, translocation, and mutation of the cellular pathways that regulate its stability. Inhibition of the Myc oncogene by various modalities has had limited success. One Myc inhibitor, Omomyc, has limited cellular and in vivo activity. Here, we report a mini‐protein, referred to as Mad, which is derived from the cellular Myc antagonist Mxd1. Mad localizes to the nucleus in cells and is 10‐fold more potent than Omomyc in inhibiting Myc‐driven cell proliferation. Similar to Mxd1, Mad also interacts with Max, the binding partner of Myc, and with the nucleolar upstream binding factor. Mad binds to E‐Box DNA in the promoters of Myc target genes and represses Myc‐mediated transcription to a greater extent than Omomyc. Overall, Mad appears to be more potent than Omomyc both in vitro and in cells.

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Engineering the Immune Adaptor Protein STING as a Functional Carrier

Sun

et al. 2021

Advanced Therapeutics

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Activation of the stimulator of interferon genes (STING) pathway through cyclic dinucleotides (CDNs) is being explored as potent vaccine adjuvants against infectious diseases and to increase tumor immunogenicity toward cancer immunotherapy. To date, a myriad of synthetic vehicles, including liposomes, polymers, and other nanoparticle platforms, have been developed to improve the bioavailability and therapeutic efficacy of STING agonists in preclinical mouse models. Compared to synthetic materials, protein-based carriers represent an attractive delivery platform owing to their biocompatibility, amenability to genetic engineering, and intrinsic capacity to form well-defined structures. Here, the immune adaptor STING is engineered as aprotein-based delivery system for efficient encapsulation and intracellular delivery of CDNs. Through genetic fusion with a protein transduction domain, the recombinant STING can spontaneously penetrate cells to markedly enhance the delivery of CDNs in a mouse vaccination model and a syngeneic melanoma model. As certain tumor cells can evade immune surveillance via loss of STING expression, authors further unveiled that the STING platform can serve as a functional vehicle to restore the STING signaling in cell lines with impaired STING expression. Altogether, their delivery platform may offer a unique direction toward targeting STING-silenced tumors and augmenting the efficacy of STING-based vaccine adjuvants.

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Omomyc Reveals New Mechanisms To Inhibit the MYC Oncogene

Abstract: The MYC oncogene is upregulated in human cancers by translocation, amplification, and mutation of cellular pathways that regulate Myc. Myc/Max heterodimers bind to E box sequences in the promoter regions of genes and activate transcription.

Cited by 63 publications

References 50 publications

Blocking Myc to Treat Cancer: Reflecting on Two Decades of Omomyc

Blocking Myc to Treat Cancer: Reflecting on Two Decades of Omomyc

Inhibition of Myc transcriptional activity by a mini‐protein based upon Mxd1

Engineering the Immune Adaptor Protein STING as a Functional Carrier

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