Chemical Inhibitors of Anti-Apoptotic Bcl-2 Family Proteins

Sanford Burnham Prebys Medical Discovery Institute, La Jolla CA

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Abstract

Chemical inhibitors of anti-apoptotic Bcl-2-family proteins Proteins in the Bcl-2 (B-cell lymphocyte/leukemia-2) family are critical components of the intrinsic apoptotic pathway. Several homologs, as defined by sequence similarity to some or all of the four Bcl-2 homology (BH) domains in Bcl-2, are found in humans and have anti- or pro-apoptotic function. Up-regulation of anti-apoptotic Bcl-2 proteins is often associated with the onset and progression of many type of cancer. Moreover, Bcl-2 over-expressing cancer cells are resistant to traditional, chemotherapy and radiation, therapeutic strategies that rely on the ability to induce apoptosis. Thus, novel optimized strategies for treatment of cancer might be based on molecules that neutralize the effects of the anti-apoptotic Bcl-2 proteins. In fact, Bcl-2-targeting antisense oligonucleotides (Genasense) are in Phase III clinical trials for the treatment of chronic lymphocytic leukemia, myeloma, and melanoma and in vivo studies with mouse models of human lymphomas have proven their efficacy. However, a small-molecule drug approach to targeting Bcl-2 proteins would be preferable from the standpoint of cost and convenience of delivery. Also, given that other antiapoptotic members of the Bcl-2 family, such as Bcl-xL and Mcl-1, can play important roles in apoptosis-suppression in different cancer cells, compounds that simultaneously target several anti-apoptotic Bcl-2-family proteins may be required for optimal efficacy, One strategy to suppress the anti-apoptotic effect of Bcl-2 family proteins is the disruption of their interaction with pro-apoptotic Bcl-2 family members by compounds that mimic pro-apoptotic BH3 domains. In this regard, we-have recently discovered that certain natural products with demonstrated anticancer activity are able to directly inhibit Bcl-2 and Bcl-xL in vitro and in cell via this mechanism. In this application, we propose to use a combination of modern biophysical techniques, structure-based design, and medicinal chemistry to design and synthesize novel, optimized compounds with increased drug-likeness, potency and selectivity. Our final goal is to generate novel chemical entities that demonstrate potent mechanism-based activity against anti-apoptotic Bcl-2 proteins, advancing these compounds into in vitro cell-based and in vivo tumor xenograft models, therefore providing a solid platform towards the design of novel therapies for the treatment of cancer.