Luminescence complementation technology for the identification of MYC:TRRAP inhibitors
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// Edmond J. Feris 1 , 2 , John W. Hinds 1 , 2 and Michael D. Cole 1 , 2 1 Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth College, Hanover, NH 03755, USA 2 Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA Correspondence to: Michael D. Cole, email: mcole@dartmouth.edu Keywords: cancer; drug discovery; targeted therapy; oncogene; transcription factor Received: May 15, 2021 Accepted: September 04, 2021 Published: PUBLISHED_DATE Copyright: © 2021 Feris et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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.
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Despite the disordered nature of the Myc TAD, evidence suggests that MB-II becomes a well-defined structure when it interacts with TRRAP, providing an opportunity to develop inhibitors that can block Myc-TRRAP interactions and specifically target Myc-driven cancers.
“Despite the disordered nature of the Myc TAD, evidence suggests that MB-II becomes a well-defined structure when it interacts with TRRAP, providing an opportunity to develop inhibitors that can block Myc-TRRAP interactions and specifically target Myc-driven cancers.432–434”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [432]
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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
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- Authors
- Feris, E. J., Hinds, J. W., & Cole, M. D.
- Affiliations
- Dartmouth College (US)
- Corresponding author
- Cole, Michael D.
- Venue
- Oncotarget
- Publisher
- Impact Journals, LLC
- Published
- 2021-10-12
- Volume
- 12
- Issue
- 21
- Pages
- 2147-2157
- ISSN
- 1949-2553 (ISSN-L)
- PMC
- PMC8522838
- OpenAlex
- W3199277086
- Cited by
- 4
- References
- 49
- Citations by year
- 2026: 1 · 2025: 1 · 2023: 1 · 2022: 1
- FWCI
- 0.18
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by
- Locations
- Oncotarget (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Norris Cotton Cancer Center (5P30CA023108)
- National Cancer Institute (R01CA055248, P30CA023108)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- c-Myc, TRRAP, small molecule inhibitors, transcription factors, drug discovery
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