Discovery of AMG 193, an MTA-Cooperative PRMT5 Inhibitor for the Treatment of MTAP-Deleted Cancers

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-03-27 DOI:10.1021/acs.jmedchem.4c03121

Liping H. Pettus, Matthew Bourbeau, Nuria A. Tamayo, Albert Amegadzie, Diane Beylkin, Shon K. Booker, John Butler, Michael J. Frohn, Matthew R. Kaller, Todd Kohn, Brian A. Lanman, Kexue Li, Qingyian Liu, Vu Ma, Jose Medina, Ana E. Minatti, Patricia Lopez, Francesco Manoni, Alex Pickrell, Nicholas Weires, Jan Andersson, Sanne Cowland, Sanne Glad, Ian Sarvary, Mikkel Vestergaard, Weikun Li, Sudipa Ghimire-Rijal, Narbe Mardirossian, Susmith Mukund, Qing Chen, Mei-Chu Lo, Rachel Ngo, Jawahar Khetan, Franck Madoux, Christiana Sanders, Pooja Sharma, Paul Wang, Bernd Bruenner, Stuart McCloud, Manuel Ponce, Marcus Soto, Jan Wahlstrom, Fang Xie, Yajing Yang, Siyuan Liu, Hong Tan, Antonia Policheni, Sean Caenepeel, Katherine K. Slemmons, Brian Belmontes, Paul Hughes, Jennifer R. Allen

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Abstract

MTAP deletion occurs in 10–15% of all human cancers due to its proximity to the tumor suppressor gene CDKN2A. The loss of MTAP leads to accumulation of methylthioadenosine (MTA), which shares structural similarity to S-adenosyl methionine (SAM), the methyl donor for the cell-essential protein arginine methyltransferase 5 (PRMT5). By competing with SAM, MTA partially inhibits PRMT5, making MTAP-deleted tumors susceptible to further PRMT5 inhibition. Herein, we report the discovery of MTA-cooperative PRMT5 inhibitor AMG 193, a molecule that inhibited the proliferation of HCT116 MTAP-deleted cells with ∼40x selectivity over HCT116 MTAP-WT cells. AMG 193 was orally efficacious in mouse xenografts of endogenous MTAP-null tumors such as BxPC-3 (96% TGI @ 100 mg/kg QD) and U87MG (88% TGI @ 100 mg/kg QD). Preclinical data indicate that AMG 193 is brain-penetrant. AMG 193 is currently in Phase I/II clinical trials for the treatment of advanced MTAP-deleted solid tumors.

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.