AZ14209703

AZ14209703 is a small molecule inhibitor of protein arginine methyltransferase 5 (PRMT5) developed by AstraZeneca. It is specifically designed to target cancer cells harboring methylthioadenosine phosphorylase (MTAP) deficiency, a common genetic alteration in various malignancies including bladder urothelial carcinoma. In MTAP-deleted cells, the metabolite methylthioadenosine (MTA) accumulates and binds to PRMT5, creating a unique binding pocket. AZ14209703 exploits this by selectively binding to the PRMT5-MTA complex, thereby inducing synthetic lethality in tumor cells while sparing normal, MTAP-proficient tissues. This approach aims to provide a wider therapeutic window and reduce the hematological toxicities associated with first-generation, non-selective PRMT5 inhibitors.