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Luminescence complementation technology for the identification of MYC:TRRAP inhibitors
Edmond J Feris1,2, John W Hinds1,2, Michael D Cole1,2
1Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth College, Hanover, NH 03755, USA.
Abstract:
Mechanism-based targeted therapies have exhibited remarkable success in treating otherwise untreatable or unresectable cancers. Novel targeted therapies that correct dysregulated transcriptional programs in cancer are an unmet medical need. The transcription factor MYC is the most frequently amplified gene in human cancer and is overexpressed because of mutations in an array of oncogenic signaling pathways. 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. We propose a new strategy to inhibit MYC function by disrupting its essential interaction with TRRAP using small molecules. To achieve our goal, we developed a platform using luminescence complementation for identifying small molecules as inhibitors of the MYC:TRRAP interaction. Here we present 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.
Insights
Researchers developed a new method to find drugs targeting the MYC:TRRAP interaction, crucial for cancer cell survival. This approach aims to inhibit MYC, a key driver in many cancers, offering a novel therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Targeted therapies are revolutionizing cancer treatment, yet novel strategies are needed for cancers with dysregulated transcriptional programs.
- The MYC oncogene is frequently amplified and overexpressed in human cancers, driving tumor growth and survival.
- Cancer cells often exhibit "MYC addiction," making MYC a promising therapeutic target.
Purpose of the Study:
- To develop a novel strategy for inhibiting MYC function by disrupting its interaction with TRRAP using small molecules.
- To establish a luminescence complementation assay for identifying MYC:TRRAP interaction inhibitors.
- To validate the developed assay by assessing disruptions in TRRAP binding.
Main Methods:
- Development of a luminescence complementation platform to screen for small molecules inhibiting the MYC:TRRAP interaction.
- Engineering of MYC constructs with substitutions in the MYC homology 2 region.
- Measurement of TRRAP binding disruption to validate the assay's efficacy.
Main Results:
- Successful development of a luminescence complementation assay for MYC:TRRAP interaction inhibition screening.
- Demonstrated assay validation by measuring the impact of MYC mutations on TRRAP binding.
- Established a foundation for identifying novel small molecules targeting MYC function.
Conclusions:
- The developed assay provides a robust platform for discovering MYC-specific targeted therapies.
- Disrupting the MYC:TRRAP interaction is a viable strategy for inhibiting MYC function in cancer.
- This research opens new avenues for developing treatments for MYC-driven cancers.
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