Apogossypol Derivatives for Breast Cancer Therapy
|Institution:||The Burnham Institute for Medical Research|
Maurizo Pellecchia , Ph.D. -
|Award Cycle:||2004 (Cycle 10)||Grant #: 10WB-0194||Award: $285,764|
|Award Type:||STEP Award|
|Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure|
Initial Award Abstract (2004)
Much optimism presently surrounds the possibility for breast cancer therapy drugs that would enhance or replace available chemotherapeutic agents thus reducing or even eliminating the toxic side-effects associated with conventional chemotherapy. This optimism is based on recent identification of proteins that are specific to breast cancer cells. One such molecular target is Bcl-xL, a protein that is important in regulating "apoptosis", or programmed cell-death, the natural turnover of cells in the body. Abnormally high levels of Bcl-xL in breast cancer cells inhibit apoptosis, thus providing malignant cells with a selective growth advantage and allowing proliferation in the face of radiation or chemotherapy. Here we propose to develop Bcl-xL inhibitors that, in turn, will lead to development of anti-cancer drugs that would selectively kill cancer cells while normal cells are spared. We have recently discovered that Gossypol, a natural product with demonstrated anti-breast cancer activity, exerts its function by selectively blocking Bcl-xL. Based on our knowledge on the molecular level, we have identified a new compound analogue, Apogossypol, with less toxicity in normal versus cancer cells. Based on these exciting results, we propose to design and optimize novel analogues starting from our new compound, Apogossypol, with improved potency and anti-cancer activity and possibly reduced even further side effects. Such compounds would have immediate impact in breast cancer therapy both by selectively killing breast cancer cells and by rendering them more susceptible to traditional chemotherapeutic agents. Identification, design and optimization of novel Apogossypol analogues for potential anti-breast cancer use will be performed initially in the test tube using purified Bcl-xL protein. We are capable of rapidly testing for chemical compounds that are able to inhibit the function of Bcl-xL in vitro on purified protein and in cell-based assays with human breast cancer cell lines. We will combine traditional medicinal chemistry with modern drug optimization strategies based on techniques called nuclear magnetic resonance spectroscopy and computer modeling. These techniques have already enabled us to design Apogossypol thus eliminating the chemical substructures of its parent compound that may produce toxic effects in humans. Similar strategies will be used to obtain more potent and safer compounds. Natural remedies such as Gossypol possess many distinctive properties and can be often very useful in therapy. However, the lack on knowledge of the specific molecular targets and the precise mechanism of action, often limit further optimization. By using a combination of modern biophysical techniques based on nuclear magnetic resonance spectroscopy we have now identified the molecular target of Gossypol and derived a parent compound, Apogossypol which shows less toxicity in normal versus cancer cells. This discovery paves the way for design and synthesis of novel Apogossypol analogs with possibly even higher affinity and selectivity for Bcl-xL and reduced toxicity for normal cells. We are confident that our approach of combining traditional medicinal chemistry with modern and innovative biophysical techniques will lead to more effective drugs for immediate use in the fight against breast cancer.
Final Report (2006)
Much optimism currently surrounds the possibility of finding selective drugs for breast cancer therapy that will either work in concert with the available chemotherapeutic agents or even replace them thus eliminating the toxic side-effects associated with conventional chemotherapy. This hope is based on uncovering many novel molecular targets that are specific to certain cancer cells, which will allow the targeting of cancer cells while normal cells are spared. In breast cancer, one such target is the protein called Bcl-xl. This protein is part of a family of proteins called Bc1-2, which are very important for regulation of the naturally occurring turnover of cells in the body, called programmed cell-death or "apoptosis". The proteins prevent cancer cell death providing malignant cells with a selective growth advantage, allowing proliferation in the face of radiation or chemotherapy. We have begun an aggressive campaign towards the identification and optimization of novel Bcl-xl antagonists that could be used either as single pro-apoptotic agents or in combination with conventional agents thus functioning as chemisensitizers. Our lead compounds are the natural products Gossypol and Apogossypol that were discovered in our laboratories recently as potent and effective Bcl-xL antagonists. During the course of funding, our focus has been to determine proper routes for optimizing Apogossypol as chemotherapeutic agent. First, we have designed and synthesized a number of compounds that contain chemical substructures that are important for the activity of Apogossypol. While these molecules presented reduced activity, they represent valid starting point for further iterative optimizations. We have focused on trying to obtain novel compounds by direct modification of Apogossypol and Gossypol. Furthermore, we have moved forward our studies with Apogossypol itself and produced a number of comparative studies to assess its stability, in vivo efficacy and toxicity when compared to Gossypol. Interestingly, Apogossypol was found to be superior to Gossypol in terms of plasma stability, pharmacokinetics in mice and efficacy in a Bcl-2 transegenic mouse model used to evaluate the efficacy of Bcl-2 antagonists. Most striking however, is the fact that while we found that Gossypol is relatively toxic to mice (mostly liver and GI toxicity), Apogossypol is very well tolerated. All together, our data support our original hypothesis that Apogossypol is a viable compound for the development of novel anti-cancer therapies. A suitable formulation for the compound has also been accomplished and in vivo studies on its oral efficacy are also very encouraging. A lot remains to be accomplished in terms of demonstrating the efficacy of the compound in combination.