Apogossypol Derivatives for Breast Cancer Therapy
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: 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.