DS5361

DS5361 is an orally available, potentially first-in-class small-molecule inhibitor of SMG1, a serine/threonine kinase that is a key component of the nonsense-mediated mRNA decay (NMD) pathway. Developed by Daiichi Sankyo, DS5361 is being investigated for the treatment of advanced or metastatic solid tumors, particularly those with high tumor mutational burden (TMB-H) or high microsatellite instability (MSI-H). By inhibiting NMD, the drug prevents the degradation of mRNAs containing premature termination codons, such as those resulting from frameshift mutations, thereby increasing the expression of tumor-specific neoantigens. This mechanism is intended to stimulate antitumor immunity and enhance the efficacy of immune checkpoint inhibitors like pembrolizumab.