Blocking Myc to Treat Cancer: Reflecting on Two Decades of Omomyc
Abstract
:1. Introduction
1.1. Myc
1.2. Myc in Cancer
1.3. Myc as a Therapeutic Target
- The three Myc family members, MYC, MYCN, and MYCL, are partially-redundant transcription factors, so that Myc-inhibitory strategies, ideally, should target them all to obtain the most efficient therapeutic impact.
- Myc is an intrinsically disordered, non-enzymatic protein; hence, conventional small molecules that target highly conserved, fixed three-dimensional structures like ATP-binding pockets in kinases cannot be discovered or designed.
- Myc exerts its function in the nucleus of the cell, an elusive compartment to conventional therapeutics.
2. Omomyc Design and Characterization
2.1. Omomyc as a Myc Dominant Negative
2.2. Omomyc’s Role in Myc-induced Transactivation and Transrepression
2.3. Omomyc and Epigenetic Markers
2.4. Omomyc and Stemness
3. Omomyc as a Proof of Concept that Myc Inhibition is a Viable Therapeutic Option
3.1. Omomyc Efficacy In Vitro
3.2. Omomyc Efficacy and Side Effects In Vivo
4. From Proof of Concept to Pharmacological Approach
4.1. Recombinant Omomyc is a Cell-penetrating Peptide
4.2. The Omomyc Mini-Protein Behaves as its Transgenically-expressed Counterpart in Cancer Cells
4.3. Intranasal or Intravenous Administration of Omomyc is Safe and Efficacious In Vivo
5. Ongoing Research and Future Directions
5.1. Omomyc Fusion with “Phylomers”
5.2. Inclusion Bodies
5.3. Variants of Omomyc
5.4. Other bHLHLZ Mini-Proteins
6. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Type of Variant | Main Differences with Omomyc | Efficacy in vitro | Efficacy in vivo | Efficacy and Lack of Toxicity after Systemic Administration |
---|---|---|---|---|
Omomyc [79] | √ | √ | √ | |
FPPa-Omomyc [85,86] | Efficacious at lower concentrations | √ | √ | Not reported |
Omomyc-FNI/II/IV-H6 inclusion bodies [87] | Slow release Targeted to CD44+ cells | √ | Some | Not reported |
[AQ]Omomyc(SH) [88] | Enhanced cell penetration | Not reported | Not reported | Not reported |
Shorter Omomyc derivatives with enhanced DNA binding activity [89] | Much shorter than Omomyc Not able to dimerize with Myc or MAX | √ | Not reported | Not reported |
Mad (not derived from Omomyc) [90] | Binds to MAX but not Myc Protected from ubiquitination More potent than Omomyc in vitro | √ | Not reported | Not reported |
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Massó-Vallés, D.; Soucek, L. Blocking Myc to Treat Cancer: Reflecting on Two Decades of Omomyc. Cells 2020, 9, 883. https://doi.org/10.3390/cells9040883
Massó-Vallés D, Soucek L. Blocking Myc to Treat Cancer: Reflecting on Two Decades of Omomyc. Cells. 2020; 9(4):883. https://doi.org/10.3390/cells9040883
Chicago/Turabian StyleMassó-Vallés, Daniel, and Laura Soucek. 2020. "Blocking Myc to Treat Cancer: Reflecting on Two Decades of Omomyc" Cells 9, no. 4: 883. https://doi.org/10.3390/cells9040883