cc214-2 and Prostatic-Neoplasms

We report here the synthesis and structure-activity relationship (SAR) of a novel series of mammalian target of rapamycin (mTOR) kinase inhibitors. A series of 4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones were optimized for in vivo efficacy. These efforts resulted in the identification of compounds with excellent mTOR kinase inhibitory potency, with exquisite kinase selectivity over the related lipid kinase PI3K. The improved PK properties of this series allowed for exploration of in vivo efficacy and ultimately the selection of CC-223 for clinical development.

Topics: Animals; Antineoplastic Agents; Drug Discovery; Humans; Male; Models, Molecular; Molecular Structure; Phosphoinositide-3 Kinase Inhibitors; Prostatic Neoplasms; Protein Kinase Inhibitors; Pyrazines; Rats; Signal Transduction; Structure-Activity Relationship; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

We report here the discovery of a novel series of selective mTOR kinase inhibitors and the identification of CC214-2, a compound with demonstrated anti-tumor activity upon oral dosing in a PC3 prostate cancer xenograft model. A series of 4,6-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones were discovered through a core modification of our original compound series. Analogs from this series have excellent mTOR potency and maintain selectivity over the related PI3Kα lipid kinase. Compounds such as CC214-2 were found to block both mTORC1(pS6) and mTORC2(pAktS473) signaling in PC3 cancer cells, in vitro and in vivo.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Evaluation, Preclinical; Half-Life; Humans; Male; Mice; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Prostatic Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrazines; Signal Transduction; TOR Serine-Threonine Kinases; Transplantation, Heterologous