Discovery of AMG 193, an MTA-Cooperative PRMT5 Inhibitor for the Treatment of <i>MTAP</i>-Deleted Cancers
Liping H. Pettus, Matthew P. Bourbeau, Nuria Tamayo, Albert Amegadzie, Diane Beylkin, Shon K. Booker, John Butler, Michael Frohn, Matthew R. Kaller, Todd J. Kohn, Brian A. Lanman, Kexue Li, Qingyian Liu, Vu Ma, Jose M. Medina, Ana Minatti, Patrícia Luciana da Costa Lopez, Francesco Manoni, Alex Pickrell, Nicholas A. Weires, Jan Andersson, Sanne Cowland, Sanne Glad, Ian Sarvary, M. 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 A. Bruenner, S.J. McCloud, Manuel Antonio Díaz de León Ponce, Marcus Soto, Jan L. Wahlstrom, Fang Xie, Yajing Yang, Siyuan Liu, Hong Tan, Antonia N. Policheni, Sean Caenepeel, Katherine K. Slemmons, Brian Belmontes, Paul Hughes, Jennifer R. Allen
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.