An intricate network of protein-protein interactions between pro-apoptotic and anti-apoptotic Bcl-2 family proteins maintains a balance between cell survival and cell death. The sequestration of pro-apoptotic proteins by the anti-apoptotic Bcl-2 family proteins suppresses mitochondrial damage and ensures cell survival. Increased levels of anti-apoptotic proteins (Bcl-2, Bcl-xL or Mcl-1) are associated with maintenance of malignant diseases, resistance to chemotherapy and poor clinical outcome. Modulating the function of anti-apoptotic proteins using small molecules as a therapeutic strategy has attracted much attention in recent years.  ABT-737, a small molecule Bcl-2/Bcl-xL inhibitor suppresses tumor growth and sensitizes cancers to chemotherapeutic agents in preclinical models. However, cancer cells that express high levels of Mcl-1 are refractory to ABT-737 treatment.  Down regulation of Mcl-1 sensitizes cells to ABT-737.To identify small molecules with anti-proliferative activity we screened focused libraries of privileged scaffolds. This resulted in the identification of quinoxaline analogs with low-micromolar potency in growth inhibition assays. To determine the mechanistic basis for the observed growth inhibition a subset of compounds were evaluated for Mcl-1 dependent caspase activation. The best compound, identified from the screen was validated as a specific Mcl-1 modulator. We also show that best compound with ABT-737 synergistically inhibited growth and induced apoptosis. A second iteration of synthesis and screening identified critical functional groups on the quinoxaline core that are required for biological activity. This also led to the identification two additional analogs as Mcl-1 modulators. These are currently being explored in preclinical models.

Small molecule Mcl-1 pathway inhibitor and ABT-737 synergistically inhibit growth and induce apoptosis

243rd National Meeting (2012)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.