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

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

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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
Volume10
Issue number1
DOIs
StatePublished - 2002

Fingerprint

Sirolimus
Phosphatidylinositol 3-Kinases
Ataxia Telangiectasia
Phosphotransferases
Derivatives
Lactones
Inhibitory Concentration 50
Ataxia Telangiectasia Mutated Proteins
Structure-Activity Relationship
Tumor Cell Line
Radio
Tumors
Cells
Molecules
quinoline
Therapeutics
Growth
Pharmaceutical Preparations

ASJC Scopus subject areas

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

Cite this

Novel pyrrolo-quinoline derivatives as potent inhibitors for PI3-kinase related kinases. / Peng, Hairuo; Kim, Doeg I.; Sarkaria, Jann N; Cho, Yong S.; Abraham, Robert T.; Zalkow, Leon H.

In: Bioorganic and Medicinal Chemistry, Vol. 10, No. 1, 2002, p. 167-174.

Research output: Contribution to journalArticle

Peng, Hairuo ; Kim, Doeg I. ; Sarkaria, Jann N ; Cho, Yong S. ; Abraham, Robert T. ; Zalkow, Leon H. / Novel pyrrolo-quinoline derivatives as potent inhibitors for PI3-kinase related kinases. In: Bioorganic and Medicinal Chemistry. 2002 ; Vol. 10, No. 1. pp. 167-174.
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