Peter Kalev, Marc L Hyer, Stefan Gross, Zenon Konteatis, Chi-Chao Chen, Mark Fletcher, Max Lein, Elia Aguado-Fraile, Victoria Frank, Amelia Barnett, Everton Mandley, Joshua Goldford, Yue Chen, Katie Sellers, Sebastian Hayes, Kate Lizotte, Phong Quang, Yesim Tuncay, Michelle Clasquin, Rachel Peters, Jaclyn Weier, Eric Simone, Joshua Murtie, Wei Liu, Raj Nagaraja, Lenny Dang, Zhihua Sui, Scott A Biller, Jeremy Travins, Kevin M Marks, Katya Marjon
The methylthioadenosine phosphorylase (MTAP) gene is located adjacent to the cyclin-dependent kinase inhibitor 2A (CDKN2A) tumor-suppressor gene and is co-deleted with CDKN2A in approximately 15% of all cancers. This co-deletion leads to aggressive tumors with poor prognosis that lack effective, molecularly targeted therapies. The metabolic enzyme methionine adenosyltransferase 2α (MAT2A) was identified as a synthetic lethal target in MTAP-deleted cancers. We report the characterization of potent MAT2A inhibitors that substantially reduce levels of S-adenosylmethionine (SAM) and demonstrate antiproliferative activity in MTAP-deleted cancer cells and tumors...
February 8, 2021: Cancer Cell