Novel pyrrolo-quinoline derivatives as potent inhibitors for PI3-kinase related kinases

Abstract

Several pyrrolo-quinoline gamma -lactones were found as novel inhibitors for two members of the PI3-kinase related kinase (PIKK) family, Ataxia-Telangiectasia-mutated (ATM) protein and the mammalian Target of Rapamycin (mTOR). Preliminary structure-activity relationship studies indicated that an electrophilic exocyclic double bond conjugated to the carbonyl group of the gamma -lactone ring was crucial for the PIKK inhibitory potency. One of the best ATM inhibitors in this series, DK8G557, showed IC50 values of 0.6 and 7.0 muM for ATM and mTOR, respectively. This compound exhibited potent and selective growth inhibition activities in the NCI 60 human tumor cell line screen with a GI(50) MG-MID value of 2.69 muM. The best mTOR inhibitor in this series, HP9912, exhibited IC50 values of 0.5 and 6.5 muM for mTOR and ATM, respectively. These compounds suggest novel leads for the discovery of potent small molecule inhibitors of PIKKs as potential anticancer drugs, with therapeutic activities as either single, or as sensitizing agents to conventional radio-, or chemo-therapeutic strategies. (C) 2001 Elsevier Science Ltd. All rights reserved.