Bcl-2 and the related protein Bcl-xL act as "brakes" on programmed cell death, or apoptosis, and are key regulators of this process. Many cancer cells have higher than normal levels of Bcl-2 and/or Bcl-xL. This allows them to evade cell death, or apoptosis, and potentially become resistant to chemotherapy. We are developing compounds that target Bcl-2 alone, and Bcl-2/Bcl-xL together, to inhibit their protective effect on cancer cells. Inhibitors of Bcl family proteins may work as single agents in B-cell malignancies that are dependent on Bcl-2 for their survival, such as follicular lymphoma, chronic lymphocytic leukemia, and diffuse large B-cell lymphoma. Bcl inhibitors are also expected to work in combination with chemotherapies to sensitize a broad range of solid tumors to treatment with chemotherapy.

Disruption of the protein-protein interaction between Bcl-2 and its pro-apoptotic ligand by an INFI compound

We have developed highly potent compounds that either selectively target Bcl-2 or target both Bcl-2 and Bcl-xL. In cells, these compounds disrupt the protein-protein interactions between Bcl-2 and its pro-apoptotic binding partners and selectively induce apoptosis in cancer cells that depend on Bcl-2 for survival. In preclinical studies in a variety of tumor types, antagonism of Bcl-2 using our compounds also results in synergy with multiple chemotherapeutic agents. These drug candidates are currently in lead optimization in collaboration with Novartis.