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