published "Luminescence complementation technology for the identification of MYC:TRRAP inhibitors" which reported that the fact that many cancer cells cannot survive without MYC – a phenomenon termed «MYC addiction» – provides a compelling case for the development of MYC-specific targeted therapies.
These authors propose a new strategy to inhibit MYC function by disrupting its essential interaction with TRRAP using small molecules. Here they offer validation of this assay by measuring the disruption of TRRAP binding caused by substitutions to the invariant and essential MYC homology 2 region of MYC.
Dr. Michael D. Cole from The Geisel School of Medicine at Dartmouth College as well as The Dartmouth-Hitchcock Medical Center said, "Recent years have been marked by a focused recalibration of drug discovery engines in the pharmaceutical and biotechnology worlds."
Rising costs of research and development hinder the pursuit of targets without the greatest substantial value. Historical failure coupled with low probability of success and lack of novel approaches have focused efforts into the pursuit of new therapeutic strategies. However, mechanism-based targeted therapies have exhibited remarkable success in treating otherwise untreatable or unresectable cancers. Amongst these, the most successful are chemical or biological entities that specifically target cancerous cellular states and have minimal effects on normal cellular programs.
However, it does have a functional DNA-binding domain and a transactivation domain. The DNA-binding domain requires a protein-protein interaction with its obligate partner MAX. Several labs have attempted to find small molecules that inhibit MYC:MAX with limited success. It is informative to point out the timeline of MYC:MAX inhibitor research. The MYC:TRRAP interaction occurs at a precise motif in the TAD of MYC known as the MYC Homology Box 2. The importance of MB2 in MYC-driven tumorigenesis is well established in cellular assays and animal models, presumably because it is necessary for the MYC:TRRAP interaction. Therefore, the TAD of MYC, MB2, and MYC:TRRAP are required for MYC-driven transactivation and cancer promotion.
The Cole Research Team concluded in their Oncotarget Research Output that GCN5 and Tip60 have been reported to acetylate histone tails in vitro but cannot do so for an assembled nucleosome. Given these observations and TRRAP's HEAT domain structural similarities with that of DNA-PKcs, TRRAP could be required for efficient HAT activity because it enables the presentation of lysine tails by denaturing nucleosomes. This model provides a rationale for TRRAP essentiality in MYC cancer biology.
DOI - https://doi.org/10.18632/oncotarget.28078
Full text - https://www.oncotarget.com/article/28078/text/
