Design and Testing of Bi-Functional, P-Loop-Targeted MDM2 Inhibitors
Abstract
This proposal is to design and evaluate a novel class of bifunctional MDM2 inhibitors, based on the discovery that nucleotides can bind to the P-loop of MDM2 and cause its relocalization to the nucleolus. Such bifunctional compounds will be designed to target MDM2, but not other P-loop-containing proteins. This approach represents a new strategy for the inhibition of MDM2 function and the treatment of breast cancer. During the first year of this grant we have (1) cloned and expressed GST-fused Mdm2 wild-type RING domain and its point mutations; (2) procured and tested all commercially available fluorescently labeled ATP analogs and identified 2 specific high affinity binders to the Mdm2 RING domain; (3) created a structure-activity relationship model (SAR) of the Mdm2 RING domain based on filter binding data of known ATP analogs for use in structure-based virtual screening; (4) developed high-throughput filters to exclude toxic and reactive compounds from commercial compound libraries, and (5) performed virtual screen on pre-filtered compound libraries and retrieved 800 candidate compounds for testing. Going forward we will build on these accomplishments to identify and optimize novel compounds that interact with and inhibit the E3 ligase activity of Mdm2.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2006
- Accession Number
- ADA457474
Entities
People
- Carol L. Prives
Organizations
- Columbia University