Lead Optimization of N-3-Substituted 7-Morpholinotriazolopyrimidines as Dual Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Inhibitors: Discovery of PKI-402

Abstract

Herein we describe the identification and lead optimization of triazolopyrimidines as a novel class of potent dual PI3K/mTOR inhibitors, resulting in the discovery of 3 (PKI-402). Compound 3 exhibits good physical properties and PK parameters, low nanomolar potency against PI3Kalpha and mTOR, and excellent inhibition of cell proliferation in several human cancer cell lines. Furthermore, in vitro and in vivo biomarker studies demonstrated the ability of 3 to shut down the PI3K/Akt pathway and induce apoptosis in cancer cells. In addition, 3 showed excellent in vivo efficacy in various human cancer xenografts, validating suppression of PI3K/mTOR signaling as a potential anticancer therapy.

Combined 3D-QSAR and Molecular Docking Study on benzo[h][1,6]naphthyridin-2(1H)-one Analogs as mTOR Inhibitors

“…The binding mode shows the designed compounds have a good effect with the mTOR receptor. In this work, the study of benzo[h] [1,6] naphthyridin-2(1H)-one analogues compounds of mTOR inhibitors based on 3D-QSAR and molecular docking model have been analysed in detail. The combined fields of CoMFA and CoMSIA were be used to analyse the structure-activity relationship of these compounds and then getting a stable and direct model.…”

“…Based on a detailed analysis of QSAR and molecular docking, ten novel mTOR inhibitors were designed, and then the activity of these compounds were predicted. Together with the 3D-QSAR and molecular docking study, more information about the transformation of the benzo[h] [1,6] naphthyridin-2(1H)-one scaffold compounds could be provided, these studies offer guidelines for designing higher activity mTOR inhibitors with novel structures. …”

“…Fifty five benzo[h] [1,6] naphthyridin-2(1H)-one analogs of mTOR protein inhibitors came from the literature [23,24] . The total set was divided into training set (contain 40 compounds) and testing set (contain 15 compounds), the testing set compounds were marked with an asterisk.…”

“…There are two different mTOR proteins in cells namely mTORC 1 and mTORC 2 . mTORC 1 protein complex is responsible for regulating protein synthesis and cell cycle progressing [4,5] , mTORC 2 protein complex can participate in cell cytoskeleton formation and survival [6,7] . Research shows that mTOR signal transduction pathway was activated abnormally in the tumor.…”

“…For nearly a decade, the QSAR and molecular docking study of PI3K/Akt/mTOR pathway small molecule inhibitors have made great progress in drugs development, many novel mTOR inhibitors were used in clinical treatment [21,22] . In the study, to acquire highly predictive model of benzo[h] [1,6] naphthyridin-2(1H)-one analogs on the inhibition of mTOR kinase, the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods were used to establish the 3D-QSAR model, and then the conformations of binding model were analysed by molecular docking. The QSAR and molecular docking models could provide insights into the interrelation between the chemical structure information of the small molecule and mTOR protein receptor, which can offer information for us to transform these compounds.…”