Perturbing pro-survival proteins using quinoxaline derivatives: A structure-activity relationship study

Rajkumar Rajule, Vashti C. Bryant, Hernando Lopez, Xu Luo, Amarnath Natarajan

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

In HeLa cells the combinatorial knockdown of Bcl-xL and Mcl-1 is sufficient to induce spontaneous apoptosis. Quinoxaline derivatives were screened for the induction of Mcl-1 dependent apoptosis using a cell line without functional Bcl-xL. Quinoxaline urea analog 1h was able to specifically induce apoptosis in an Mcl-1 dependent manner. We demonstrate that even small changes to 1h results in dramatic loss of activity. In addition, 1h and ABT-737 synergistically inhibit cell growth and induce apoptosis. Our results also suggest that 1h could have therapeutic potential against ABT-737 refractory cancer.

Original languageEnglish (US)
Pages (from-to)2227-2234
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number7
DOIs
StatePublished - Apr 1 2012

Keywords

  • ABT-737
  • Bcl-xL
  • Mcl-1
  • Quinoxaline
  • Structure-activity relationship

ASJC Scopus subject areas

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

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