ABSTRACT
BACKGROUND: Lung cancer is the major cause of cancer-related deaths and many cases of Non Small Cell Lung Cancer (NSCLC), a common type of lung cancer, have frequent genetic/oncogenic activation of EGFR, KRAS, PIK3CA, BRAF, and others that drive tumor growth. Some patients though initially respond, but later develop resistance to erlotinib/gefitinib with no option except for cytotoxic therapy. Therefore, development of novel targeted therapeutics is imperative to provide improved survival benefit for NSCLC patients. The mTOR cell survival pathway is activated in naïve, or in response to targeted therapies in NSCLC. METHODS: We have discovered P7170, a small molecule inhibitor of mTORC1/mTORC2/ALK1 and investigated its antitumor efficacy using various in vitro and in vivo models of human NSCLC. RESULTS: P7170 inhibited the phosphorylation of AKT, S6 and 4EBP1 (substrates for mTORC2 and mTORC1) levels by 80-100% and growth of NSCLC cells. P7170 inhibited anchorage-independent colony formation of NSCLC patient tumor-derived cells subsistent of disease sub-types. The compound also induced apoptosis in NSCLC cell lines. P7170 at a well-tolerated daily dose of 20 mg/kg significantly inhibited the growth of NSCLC xenografts independent of different mutations (EGFR, KRAS, or PIK3CA) or sensitivity to erlotinib. Pharmacokinetic-pharmacodynamic (PK-PD) analysis showed sub-micro molar tumor concentrations along with mTORC1/C2 inhibition. CONCLUSIONS: Our results provide evidence of antitumor activity of P7170 in the erlotinib -sensitive and -insensitive models of NSCLC.
Subject(s)
Activin Receptors, Type II/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Cell Proliferation/drug effects , Imidazoles/pharmacology , Lung Neoplasms/drug therapy , Multiprotein Complexes/antagonists & inhibitors , Quinolines/pharmacology , TOR Serine-Threonine Kinases/antagonists & inhibitors , Animals , Apoptosis/drug effects , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Line, Tumor , Class I Phosphatidylinositol 3-Kinases , Drug Resistance, Neoplasm/drug effects , ErbB Receptors/pharmacology , Erlotinib Hydrochloride , HeLa Cells , Humans , Lung Neoplasms/metabolism , Male , Mechanistic Target of Rapamycin Complex 1 , Mechanistic Target of Rapamycin Complex 2 , Mice , Mice, Nude , Phosphatidylinositol 3-Kinases/pharmacology , Phosphorylation/drug effects , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins/pharmacology , Proto-Oncogene Proteins p21(ras) , Quinazolines/pharmacology , ras Proteins/pharmacologyABSTRACT
We report our attempts at improving the oral efficacy of low-nanomolar inhibitors of xanthine oxidase from isocytosine series through chemical modifications. Our lead compound had earlier shown good in vivo efficacy when administered intraperitoneally but not orally. Several modifications are reported here which achieved more than twofold improvement in exposure. A compound with significant improvement in oral efficacy was also obtained.
Subject(s)
Cytosine/analogs & derivatives , Enzyme Inhibitors/chemistry , Xanthine Oxidase/antagonists & inhibitors , Administration, Oral , Animals , Catalytic Domain , Cytosine/administration & dosage , Cytosine/chemistry , Cytosine/pharmacology , Enzyme Activation/drug effects , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacology , Inhibitory Concentration 50 , Models, Animal , Models, Molecular , Molecular Structure , RatsABSTRACT
Structure-activity relationship studies were carried out for lead generation following structure-guided design approach from an isocytosine scaffold identified earlier for xanthine oxidase inhibition. A 470-fold improvement in in vitro IC(50) was obtained in the process. Five most potent compounds with nanomolar IC(50) values were selected for pharmacokinetics and in vivo experiments. The best compound showed good in vivo activity when administered intraperitoneally but was not active by oral route. The results suggest that improvement in oral exposure could improve the in vivo efficacy of this series.
