Abstract
c-MYC is an oncogenic transcription factor that plays a crucial role in the regulation of downstream targets involved in proliferation, apoptosis, differentiation, metabolism, signaling, and immune response processes whose deregulation leads to the progression of different pathologies. The development of selective and potent small-molecule inhibitors of c-MYC remains a grand challenge in chemical biology and medicine due to its undruggability, derived from extensive intrinsic disorder. In this study, we identified a novel dihydro pyrazolo pyridinone scaffold, MY05, that selectively targets c-MYC in cells and disrupts MYC-MAX interaction. MY05 engages intracellular c-MYC, modulates c-MYC thermal stability, reduces c-MYC transcriptional targets, and inhibits proliferation in cancer cells and tumor growth in mice. In summary, we identified a novel compound that directly interacts with c-MYC to disrupt the transcriptional program.
| Original language | English |
|---|---|
| Pages (from-to) | 6233-6251 |
| Number of pages | 19 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 68 |
| Issue number | 6 |
| DOIs | |
| State | Published - Mar 27 2025 |
Bibliographical note
Publisher Copyright:© 2025 American Chemical Society.
Funding
This work was supported by the National Science Foundation Chemistry of Life Processes (NSF-CLP) grant for S.G.A. (Award CHE-2203559). The authors would like to thank the following facilities at the University of Kentucky who provided support in completion of the experiments detailed in this manuscript. The UK NMR Center is supported by NSF (CHE-997738). This research was supported by the Cancer Research Informatics Shared Resource of the University of Kentucky Markey Cancer Center (P30CA177558). The authors also acknowledge the support of the Center for Pharmaceutical Research and Innovation (NIH P20GM130456). For the flow cytometry experiments, the authors thank UK Flow Cytometry, Pathology and Immune Function core supported by the Office of the Vice President of Research, Markey Cancer Center, and NCI Center Core Support Grant (P30 CA177558). The authors thank Prof. Giovanni Zinzalla at Karolinska Institutet (Stockholm, Sweden) for the MYC plasmid used. Thanks to Dr. Yadi Wu (University of Kentucky) and Dr. Anne Le (Johns Hopkins University) for the generous gifts of MCF-7 and P493-6 cells, respectively.
| Funders | Funder number |
|---|---|
| Center for Pharmaceutical Research and Innovation, University of Kentucky | |
| University of Kentucky | |
| Office of the Executive Vice President for Research and Partnerships, Purdue University | |
| Karolinska Institutet | |
| Neurosciences Foundation | CHE-997738 |
| Neurosciences Foundation | |
| The Johns Hopkins University | P493-6 |
| The Johns Hopkins University | |
| National Institutes of Health (NIH) | P20GM130456 |
| National Institutes of Health (NIH) | |
| National Childhood Cancer Registry – National Cancer Institute | P30 CA177558 |
| National Childhood Cancer Registry – National Cancer Institute | |
| University of Kentucky Markey Cancer Center | P30CA177558 |
| University of Kentucky Markey Cancer Center | |
| National Science Foundation Chemistry of Life Processes | CHE-2203559 |
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
