Peng, HR Kim, DI Sarkaria, JN Cho, YS Abraham, RT Zalkow, LH 2024-01-21T11:13:57Z 2024-01-21T11:13:57Z 2021-09-01 2002-01 0968-0896 https://pubs.kist.re.kr/handle/201004/139904 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. English PERGAMON-ELSEVIER SCIENCE LTD DEPENDENT PROTEIN-KINASE MAMMALIAN TARGET 3-KINASE INHIBITION DNA-DAMAGE WORTMANNIN RAPAMYCIN LY294002 CELLS PHOSPHORYLATION MECHANISM Novel pyrrolo-quinoline derivatives as potent inhibitors for PI3-kinase related kinases Article 10.1016/S0968-0896(01)00260-7 1 BIOORGANIC & MEDICINAL CHEMISTRY, v.10, no.1, pp.167 - 174 BIOORGANIC & MEDICINAL CHEMISTRY 10 1 167 174 scie scopus 000172737000018 Biochemistry & Molecular Biology Chemistry, Medicinal Chemistry, Organic Biochemistry & Molecular Biology Pharmacology & Pharmacy Chemistry Article DEPENDENT PROTEIN-KINASE MAMMALIAN TARGET 3-KINASE INHIBITION DNA-DAMAGE WORTMANNIN RAPAMYCIN LY294002 CELLS PHOSPHORYLATION MECHANISM PI3-kinase