Discovery of AMG 193, an MTA-Cooperative PRMT5 Inhibitor for the Treatment of <i>MTAP</i>-Deleted Cancers
<i>MTAP</i> deletion occurs in 10-15% of all human cancers due to its proximity to the tumor suppressor gene <i>CDKN2A</i>. The loss of MTAP leads to accumulation of methylthioadenosine (MTA), which shares structural similarity to <i>S</i>-adenosyl methionine (SAM), the methyl donor for the cell-essential protein arginine methyltransferase 5 (PRMT5). By competing with SAM, MTA partially inhibits PRMT5, making <i>MTAP</i>-deleted tumors susceptible to further PRMT5 inhibition. Herein, we report the discovery of MTA-cooperative PRMT5 inhibitor <b>AMG 193</b>, a molecule that inhibited the proliferation of HCT116 <i>MTAP</i>-deleted cells with ∼40x selectivity over HCT116 <i>MTAP</i>-WT cells. <b>AMG 193</b> was orally efficacious in mouse xenografts of endogenous <i>MTAP</i>-null tumors such as BxPC-3 (96% TGI @ 100 mg/kg QD) and U87MG (88% TGI @ 100 mg/kg QD). Preclinical data indicate that <b>AMG 193</b> is brain-penetrant. <b>AMG 193</b> is currently in Phase I/II clinical trials for the treatment of advanced <i>MTAP</i>-deleted solid tumors.
Authors
- Sudipa Ghimire-Rijal (ORCID: https://orcid.org/0000-0003-2272-4280)
- Francesco Manoni
- Sanne Glad
- Todd J. Kohn
- Mei-Chu Lo (ORCID: https://orcid.org/0000-0003-3766-2094)
- Jan L. Wahlstrom (ORCID: https://orcid.org/0000-0002-9434-1302)
- Nuria Tamayo (ORCID: https://orcid.org/0000-0002-0497-5230)
- Qingyian Liu
- Ian Sarvary
- Brian Belmontes (ORCID: https://orcid.org/0000-0003-0141-1007)
- Manuel Antonio Díaz de León Ponce
- Jan Andersson (ORCID: https://orcid.org/0009-0009-3962-4463)
- Matthew P. Bourbeau
- Brian A. Lanman (ORCID: https://orcid.org/0000-0002-8768-7188)
- Jose M. Medina
- Antonia Policheni
- Hong Tan (ORCID: https://orcid.org/0000-0003-3644-8731)
- M. Vestergaard (ORCID: https://orcid.org/0000-0002-8939-8099)
- Christiana Sanders
- S.J. McCloud
- Katherine K. Slemmons (ORCID: https://orcid.org/0000-0003-3700-5633)
- Weikun Li (ORCID: https://orcid.org/0000-0002-9525-9001)
- Rachel Ngo
- Ana Minatti (ORCID: https://orcid.org/0000-0002-8728-5832)
- Jawahar Khetan
- Franck Madoux
- Marcus Soto
- Alex Pickrell
- Albert Amegadzie
- Fang Xie (ORCID: https://orcid.org/0000-0003-1817-8125)
- Nicholas A. Weires (ORCID: https://orcid.org/0000-0003-1528-1979)
- Susmith Mukund
- Matthew R. Kaller
- Liping H. Pettus (ORCID: https://orcid.org/0000-0002-4427-6602)
- Bernd A. Bruenner (ORCID: https://orcid.org/0000-0002-3785-6035)
- Michael Frohn
- Vu Ma
- Shon K. Booker
- Paul Hughes (ORCID: https://orcid.org/0000-0002-7164-0406)
- Sanne Cowland
- Yajing Yang (ORCID: https://orcid.org/0009-0006-6950-142X)
- Narbe Mardirossian (ORCID: https://orcid.org/0000-0002-1387-0158)
- Siyuan Liu (ORCID: https://orcid.org/0000-0003-3661-6248)
- Paul C. Wang (ORCID: https://orcid.org/0000-0001-8219-7051)
- Pooja Sharma (ORCID: https://orcid.org/0000-0002-7982-9019)
- Qing Chen (ORCID: https://orcid.org/0000-0003-2425-9378)
- Patrícia Luciana da Costa Lopez (ORCID: https://orcid.org/0000-0002-0375-9181)
- Kexue Li (ORCID: https://orcid.org/0000-0002-7340-7261)
- John Butler (ORCID: https://orcid.org/0000-0001-8086-0964)
- Sean Caenepeel
- Jennifer R. Allen
- Diane Beylkin
Institutions
- Amgen (United States) (US)
- Université Bourgogne Franche-Comté (FR)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-03-27
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c03121
- Citations
- 14
- Primary Topic
- Cancer-related gene regulation
- Type
- article
- Field-Weighted Citation Impact
- 11.28