FJDEKKER04 · Combinatorial synthesis of beta-lactones and beta-lactams as potential inhibitors for Cdc25A phosphatase; an interesting target for anti-cancer drugs
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2005-07-01 → 2007-06-30
- EU contribution
- €148,021
- Participants
- 1
- Scheme
- EIF
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Results in brief
Final Activity Report Summary - FJDEKKER04 (Combinatorial synthesis of beta-lactones and beta-lactams as potential inhibitors for Cdc25A phosphatase; an interesting target for anti-cancer drugs.)
The project aimed at the development of a novel methodology to define small molecule modulators of protein function. Protein structure similarity, in conjunction with natural products, was used as inspiration source for the synthesis of a compound collection and target selection. The applicability of this new methodology was investigated and new small molecule modulators of protein function were identified. One of these small molecules was used, by the time of the project completion, in a reverse chemical genetics study to evaluate the role of the acyl protein thioesterase 1 enzyme in cell-based studies. The newly identified small molecule enabled the identification of acyl protein thioesterase 1 as a new anti-cancer drug target.
Data: CORDIS, © European Union
Project objective
Combinatorial chemistry has emerged as very powerful tool for drug discovery. However, increasing the library size does not necessarily result in many new hits and lead compounds. Because the number of thinkable organic compounds is almost infinite, there are quest arises for a biologically validated starting point in library synthesis. Natural products that bind to certain protein domains might provide such biologically validated starting points. Recent discoveries reveal that three-dimensional folds of different protein domains are often similar and that the number of distinct protein domains and families is fairly limited.Based on this it can be envisioned that natural products that bind to one member of a protein domain family can be used as a guiding principle to design ligands that bind to other members of the same protein domain family. This proposal focuses on the natural product tetrahydrolipstatin (THL) that binds to gastric and pancreatic lipase, which have high three dimensional similarity with the C dc25A phosphatase. This phosphatase has an important role in progression of the cell cycle and is thus a target for anti-cancer drug development. Combinatorial libraries inspired by the THL core structure will be assembled and screened for Cdc25A phosphatase activity, which will ultimately lead to a new generation of anti-cancer drugs.
Original text from CORDIS.
Participants
- MAX-PLANCK-INSTITUT FUR MOLEKULARE PHYSIOLOGIE · DORTMUNDCoordinatorCity levelGermany
Links
Data: CORDIS, © European Union