Novel pyrrolo-quinoline derivatives as potent inhibitors for PI3-kinase related kinases.
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 IC(50) values of 0.6 and 7.0 microM 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 microM. The best mTOR inhibitor in this series, HP9912, exhibited IC(50) values of 0.5 and 6.5 microM 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.
Peng
Hairuo
H
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332, USA. hairuo.peng@yale.edu
Kim
Doeg-Il
DI
Sarkaria
Jann N
JN
Cho
Yong-Seo
YS
Abraham
Robert T
RT
Zalkow
Leon H
LH
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000737:chemistry*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D013057:Spectrum Analysis; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011758:Pyrroles; D011804:Quinolines; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases