Combinatorial Approach for Novel Phosphatase Inhibitors
Abstract
We have synthesized more than 500 new small molecules in the Combinatorial Chemistry Center (CCC) using novel parallel approaches. We have examined the biochemical activity of these compounds as well as the Diverset, which are 2,000 compounds selected by the NCI from their 130,000+ compound library and that contain maximal chemical diversity. The 500 novel small molecules synthesized by the CCC were designed around the AC/SC pharmacophore and are based on Natural Products. Within this library, we have identified FY21-alpha-alpha 09 as the most potent inhibitor of the oncogene Cdc25. We also found that FY21-alpha-alpha 09 was an inhibitor of human malignant cell cycle transition in both G1 and G2/M phase consistent with its proposed ability to inhibit both Cdc25A, B and C. We also found that SC-alpha-alpha 69 blocked G1 and G2/M transition and caused hyperphosphorylation of cyclin-dependent kinase 1 and 4. We have used a similar approach to identify a vitamin K analog, compound 5, which is also an inhibitor of Cdc25. We have identified 5 inhibitors of Cdc25 in the NCI Diverset each having a median inhibitory concentration below 1 micro-M. They may have the potential of being new platforms for future compounds.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2000
- Accession Number
- ADA385621
Entities
People
- John S. Lazo
Organizations
- University of Pittsburgh