Discovery and Optimization of 2‑Amino-4-methylquinazoline Derivatives as Highly Potent Phosphatidylinositol 3‑Kinase Inhibitors for Cancer Treatment

Increased phosphatidylinositol
3-kinase (PI3K) signaling is among
the most common alterations in cancer, spurring intensive efforts
to develop new cancer therapeutics that target this pathway. In this
work, we discovered a series of novel 2-amino-4-methylquinazoline
derivatives through a hybridization and subsequent scaffold hopping
approach that were highly potent class I PI3K inhibitors. Lead optimization
resulted in several promising compounds (e.g., 19, 20, 37, and 43) with nanomolar PI3K
potencies, prominent antiproliferative activities, favorable PK profiles,
and robust in vivo antitumor efficacies. More
interestingly, compared with 19 and 20, 37 and 43 demonstrated improved brain penetration
and in vivo efficacy in an orthotopic glioblastoma xenograft model.
Furthermore, preliminary safety assessments including hERG channel
inhibition, AMES, CYP450 inhibition, and single-dose toxicity were
performed to characterize their toxicological properties.