Novel Combinatorial Chemistry-Derived Inhibitors of Oncogenic Phosphatases.
Abstract
Our overall goal of this US Army Breast Cancer Grant entitled "Novel Combinatorial Chemistry-Derived Inhibitors of Oncogenic Phosphatases" is to identify and develop novel therapeutic agents for human breast cancer. During the past year we synthesized a novel second generation, small molecule library designed on our previous natural product pharmacophore that was targeted against oncogenes implicated in human breast cancer, namely the dual specificity phosphatases (DSP) Cdc25. The new library maintains unique, rigid backbone structures that should provide more structural information about the active site of DSP. Several of the new compounds are potent competitive inhibitors of Cdc25. In addition we have identified the first selective VHR inhibitor, namely FY2-alpha009. This compound should facilitate our studies of the biological function of VHR, which are currently unknown. We continued our studies of the prototype member of the first combinatorial library with the best antiCdc25 activity, namely SC-alpha alpha delta89. We have determined that SC-alpha alpha 89 is selectively cytotoxic to cells, which overexpress Cdc25B due to transformation with SV-40 large T antigen. We have also discovered that SC-alpha alpha 89 disrupts a key mitogenic and antiapoptotic pathway, insulin-like growth factor-1 (lGF-1), and downregulates Cdc2 expression. SC--alpha alpha89 also blocks human breast cancer (MDA-MB-231) and other cells at G2IM consistent with Cdc25B or C inhibition. Thus, our combinatorial approach for selective DSP inhibitors remains very promising.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 1998
- Accession Number
- ADA365481
Entities
People
- John S. Lazo
Organizations
- University of Pittsburgh