Kevin M. Cottrell, Kimberly J. Briggs, A. Tsai, Colin Liang, Patrick McCarren, Douglas A. Whittington, Minjie Zhang, Wenhai Zhang, Alan Huang, Jannik Andersen, John P. Maxwell
Abstract Homozygous deletion of the methylthioadenosine phosphorylase (MTAP) gene occurs in 10–15% of all human cancers and up to 50% of high-grade malignant gliomas, representing one of the largest opportunities for precision oncology. Loss of MTAP leads to the accumulation of 5′-methylthioadenosine (MTA), which sensitizes tumor cells to inhibition of protein arginine methyltransferase 5 (PRMT5). Herein we describe the discovery of TNG456, a potent and highly selective MTA-cooperative PRMT5 inhibitor that is brain penetrant in preclinical species and currently in Phase I/II clinical studies for the treatment of advanced or metastatic solid tumors with MTAP loss, with a focus on glioblastoma.