Structural Basis for the Pharmacological Rescue of Mutant p53 With Small Molecule Compounds
Annual Summary rept. 1 Apr 2002-31 Mar 2003
PENNSYLVANIA UNIV PHILADELPHIA WISTAR INST
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The p53 protein is a tumor suppressor crucial to maintaining genomic integrity. In the event of DNA damage, p53 is responsible for transcribing genes leading to cell death. A class of mutations which occur in the core domain 102-292 leads to thermodynamic destabilization and inability to bind its cognate DNA sequence. Small molecules which bind to and stabilize mutant p53 core domain have potential to be therapeutically useful. A class of small molecules discovered via high throughput screening has been reported to bind to and stabilize the p53 core domain Foster et al.. Our results show that these compounds do not interact directly with the p53 core domain at all. Another approach using peptides as lead compounds has resulted in a class of peptides that bind to the p53 core domain with low micromolar affinity. And, in addition, has shown the ability to stabilize mutant core domain. The structure of the p53 core domain in complex with these peptides in now being actively pursued.
- Medicine and Medical Research