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

Hairuo Peng, Doeg Il Kim, Jann N. Sarkaria, Yong Seo Cho, Robert T. Abraham, Leon H. Zalkow

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


Several pyrrolo-quinoline γ-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 γ-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 μM 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 GI50 MG-MID value of 2.69 μM. The best mTOR inhibitor in this series, HP9912, exhibited IC50 values of 0.5 and 6.5 μM for mTOR and ATM, respectively. These compounds suggest novel leads for the discovery of potent small molecule inibitors of PIKKs as potential anticancer drugs, with therapeutic activities as either single, or as sensitizing agents to conventional radio-, or chemo-therapeutic strategies.

Original languageEnglish (US)
Pages (from-to)167-174
Number of pages8
JournalBioorganic and Medicinal Chemistry
Issue number1
StatePublished - 2002

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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