An Adenosine Analogue Library Reveals Insights into Active Sites of Protein Arginine Methyltransferases and Enables the Discovery of a Selective PRMT4 Inhibitor
Protein arginine methyltransferases (PRMTs) represent promising drug targets. However, the lack of isoform-selective chemical probes poses a significant hurdle in deciphering their biological roles. To address this issue, we devised a library of 100 diverse adenosine analogues, enabling a detailed exploration of the active site of PRMTs. Despite their close homology, our analysis unveiled specific chemical trends unique to the individual members. Notably, compound YD1130 demonstrated over 1000-fold selectivity for PRMT4 (IC<sub>50</sub> < 0.5 nM) over a panel of 38 methyltransferases, including the other PRMTs. Its prodrug YD1342 exhibited potent inhibition on cellular substrate methylation, breast cancer cell colony formation, and tumor growth in the animal model, surpassing or matching known PRMT4-specific inhibitors. In summary, our focused library not only illuminates the intricate active sites of PRMTs to facilitate the discovery of highly potent and isoform-selective probes but also offers a versatile blueprint for identifying chemical probes for other methyltransferases.
Authors
- Jinrong Min (ORCID: https://orcid.org/0000-0001-5210-3130)
- Nicholas Noinaj (ORCID: https://orcid.org/0000-0001-6361-2336)
- Xiaosheng Song (ORCID: https://orcid.org/0000-0003-0454-186X)
- Rong Huang (ORCID: https://orcid.org/0000-0002-1477-3165)
- Akshay S. Kulkarni (ORCID: https://orcid.org/0000-0001-5612-5118)
- Wei Xu (ORCID: https://orcid.org/0000-0003-3808-0045)
- Youchao Deng (ORCID: https://orcid.org/0000-0003-1367-2677)
- Eui‐Jun Kim (ORCID: https://orcid.org/0000-0002-8475-5229)
- Yidan Wang (ORCID: https://orcid.org/0000-0002-8138-2666)
- Michelle Bush
- Ryan X. Zhu (ORCID: https://orcid.org/0009-0007-2827-5988)
- Aiping Dong
Institutions
- University of Wisconsin–Madison (US)
- University of Toronto (CA)
- Purdue University West Lafayette (US)
- Structural Genomics Consortium (CA)
- Central China Normal University (CN)
- University of Wisconsin Carbone Cancer Center (US)
- Center for Cancer Research (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-10-03
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01041
- Citations
- 9
- Primary Topic
- Cancer-related gene regulation
- Type
- article
- Field-Weighted Citation Impact
- 2.10
Funders
- Purdue University
- Ralph W. and Grace M. Showalter Research Trust Fund
- Dr. Ralph and Marian Falk Medical Research Trust
- Natural Sciences and Engineering Research Council of Canada
- National Cancer Institute