Synthesis and structure–activity relationships of PI3K/mTOR dual inhibitors from a series of 2-amino-4-methylpyrido[2,3- d ]pyrimidine derivatives

Recent development of ATP-competitive small molecule phosphatidylinostitol-3-kinase inhibitors as anticancer agents

“…In 2014, Han et al [62] identified structurally novel and potent PI3K/mTOR dual inhibitors from a series of 2-amino-4-methylpyrido [2, 3-d] pyrimidine derivatives (145-147). As indicated by the crystal structure of PF-04691502 (122, PI3Kα /mTOR Ki = 0.57/16 nM) and GSK2126458 (143) docked into PI3Kγ, the amino-pyridopyrimidinone and quinoline formed critical hydrogen bonds with Val 882 in the hinge region.…”

QSAR modeling and structure based virtual screening of new PI3K/mTOR inhibitors as potential anticancer agents

“…Consequential altered activity of this pathway correlates directly to the development of hyperproliferative diseases and a broad spectrum of cancers including endometrial, ovarian, breast, colon, lung and other cancers [9]. Essential, independent components of this signaling pathway, PI3K and mTOR kinases, are enzymes that belong to the phosphatidylinositol-3-kinase-related kinase (PIKK) family of kinases and possess a high degree of sequence homology with the catalytic kinase domain of class I PI3Ks [6]. Therefore, PI3K and mTOR kinases present potential target places for new antineoplastics due to the apparent benefits of their dual inhibition [10,11].…”

“…PI (3,4,5)P3 is a lipid second messenger molecule that promotes the activation of Akt, a Ser/Thr kinase, the main pathway sensor responsible for the promotion of the downstream signaling events, among other things mTOR activation [1,4,5]. mTOR is a Ser/Thr kinase with a highly conserved structure; it acts through two distinctive complexes, mTORC1 and mTORC2 [6,7]. It is the main effector molecule involved into the control of cellular growth, survival and metabolism; upon activation it increases mRNA translation via activation of S6-kinase 1 and inhibition of eukaryotic translation initiation factor 4E (ieIF4E) protein [8].…”

Synthesis of 3-(4-aminophenyl) cyclopropane-1, 1,2,2-tetracarbonitrile

“…Developing an efficiently and safety method to treatment the malignancies has become a hot pot in nowadays. In recent years, many small molecule anticancer drugs had been reported [2][3][4] , such as NVP-BEZ-235, 2-methyl-2-(4-(3-methyl-2-oxo-8-(quinolin-3-yl)-2, 3-dihydro-1H-imidazo [4,5-c] quinolin-1-yl)phenyl) propanenitrile (3), 1-(4-(3-methyl-2-oxo-8-(quinolin-3-yl)-2, 3-dihydro-1H-imidazo [4,5-c]quinolin-1-yl)phenyl) cyclopropanecarbonitrile(4) [5][6] . 3-(4-aminop henyl) cyclopropane -1, 1, 2, 2 -tetracarbonitrile is the key intermediate and has a wide range of applications in the pharmaceutical and chemical fields.…”