1 research outputs found
Discovery of Clinical Development Candidate GDC-0084, a Brain Penetrant Inhibitor of PI3K and mTOR
Inhibition of phosphoinositide 3-kinase
(PI3K) signaling is an appealing approach to treat brain tumors, especially
glioblastoma multiforme (GBM). We previously disclosed our successful
approach to prospectively design potent and blood–brain barrier
(BBB) penetrating PI3K inhibitors. The previously disclosed molecules
were ultimately deemed not suitable for clinical development due to
projected poor metabolic stability in humans. We, therefore, extended
our studies to identify a BBB penetrating inhibitor of PI3K that was
also projected to be metabolically stable in human. These efforts
required identification of a distinct scaffold for PI3K inhibitors
relative to our previous efforts and ultimately resulted in the identification
of GDC-0084 (<b>16</b>). The discovery and preclinical characterization
of this molecule are described within