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

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 1 h 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, 1 h 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.

SUBMITTER: Rajule R

PROVIDER: S-EPMC3303926 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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

Rajule Rajkumar R Bryant Vashti C VC Lopez Hernando H Luo Xu X Natarajan Amarnath A

Bioorganic & medicinal chemistry 20120216 7

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 1 h 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, 1 h and ABT-737 synergistically inhibit cell growth and induce ap ...[more]

PMID: 22386982

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