Discovery of TNG462: A Highly Potent and Selective MTA-Cooperative PRMT5 Inhibitor to Target Cancers with <i>MTAP</i> Deletion
The gene encoding for MTAP is one of the most commonly deleted genes in cancer, occurring in approximately 10-15% of all human cancer. We have previously described the discovery of TNG908, a brain-penetrant clinical-stage compound that selectively targets <i>MTAP</i>-deleted cancer cells by binding to and inhibiting PRMT5 cooperatively with MTA, which is present in elevated concentrations in <i>MTAP</i>-deleted cells. Herein we describe the discovery of TNG462, a more potent and selective MTA-cooperative PRMT5 inhibitor with improved DMPK properties that is selective for <i>MTAP</i>-deleted cancers and is currently in Phase I/II clinical trials.
Authors
- Colin Liang
- Kevin M. Cottrell (ORCID: https://orcid.org/0009-0008-6511-0696)
- John P. Maxwell (ORCID: https://orcid.org/0000-0002-5969-6490)
- Shanzhong Gong (ORCID: https://orcid.org/0000-0001-8750-9907)
- Douglas A. Whittington (ORCID: https://orcid.org/0000-0002-5946-8543)
- Alan Huang (ORCID: https://orcid.org/0000-0001-5501-0212)
- Matthew R. Tonini
- Patrick McCarren (ORCID: https://orcid.org/0000-0003-2084-6655)
- Alice Tsai (ORCID: https://orcid.org/0000-0002-1939-6282)
- Minjie Zhang (ORCID: https://orcid.org/0000-0001-8561-0729)
- Wenhai Zhang (ORCID: https://orcid.org/0009-0001-7381-3462)
- Kimberly J. Briggs (ORCID: https://orcid.org/0009-0007-4564-6576)
Institutions
- Tango Therapeutics (United States) (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-03-04
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c03067
- Citations
- 21
- Primary Topic
- Cancer-related gene regulation
- Type
- article
- Field-Weighted Citation Impact
- 16.93