Use of Human Dose Prediction Metrics to Enable Discovery of AZD3470, an MTA-Cooperative PRMT5 Inhibitor in Clinical Evaluation

Inhibition of the arginine methyltransferase protein arginine methyltransferase 5 (PRMT5) has emerged as a key target for cancer therapy. Leveraging the MTAP synthetic lethality mechanism, MTA-cooperative PRMT5 inhibitors are showing promising potential as precision cancer treatments with a high therapeutic index. Herein, we report our efforts to further optimize our previously reported in vivo tool compound 1 (“AZ-PRMT5i-1”) toward a clinical candidate–quality profile, by addressing key shortcomings of this compound─limited aqueous solubility, low hERG receptor activity, and an unfavorable predicted human dose. Exploration of the terminal lactam substitution group and the central aromatic group of the isindolinone scaffold provided the key structure–activity relationship insights to meet these goals. The highest quality compounds in this series were identified by the use of a dose-to-human (D2H) automated model. These efforts resulted in the identification of 14, which shows the appropriate physicochemical properties, DMPK characteristics, and PRMT5-driven activity to be selected for progression into clinical studies.