gdc-0980 and Prostatic-Neoplasms

Selective inhibitors of mammalian target of rapamycin (mTOR) kinase based upon saturated heterocycles fused to a pyrimidine core were designed and synthesized. Each series produced compounds with K(i) < 10 nM for the mTOR kinase and >500-fold selectivity over closely related PI3 kinases. This potency translated into strong pathway inhibition, as measured by phosphorylation of mTOR substrate proteins and antiproliferative activity in cell lines with a constitutively active PI3K pathway. Two compounds exhibiting suitable mouse PK were profiled in in vivo tumor models and were shown to suppress mTORC1 and mTORC2 signaling for over 12 h when dosed orally. Both compounds were additionally shown to suppress tumor growth in vivo in a PC3 prostate cancer model over a 14 day study.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Biological Availability; Cell Line, Tumor; Drug Screening Assays, Antitumor; Female; Humans; Male; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mice; Mice, Nude; Molecular Docking Simulation; Multiprotein Complexes; Neoplasm Transplantation; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Prostatic Neoplasms; Pyrimidines; Pyrroles; Quinazolines; Structure-Activity Relationship; TOR Serine-Threonine Kinases; Transplantation, Heterologous