Related Experiment Videos
Structure based design of benzophenone-based non-thiol farnesyltransferase inhibitors
1Department für Pharmazie Zentrum f r Pharmaforschung, Ludwig-Maximilians-Universität München, München, Germany. martin.schlitzer@cup.uni-muenchen.de
Abstract:
Farnesyltransferase catalyzes the transfer of a farnesyl residue from farnesylpyrophosphate to the thiol of a cysteine side chain of proteins which carry at the C-terminus the so called CAAX-sequence. Although the exact cellular events affected by farnesyltransferase inhibiton remain to be determined, farnesyltransferase has become a major target in the development of potential anti-cancer drugs. Numerous farnesyltransferase inhibitors have been described from which the majority are CAAX-peptidomimetics possessing a free thiol group which coordinates the enzyme-bound zinc ion. The development of farnesyltransferase inhibitors is clearly directed towards the so-called non-thiol farnesyltransferase inhibitors because of adverse drug effects connected to free thiols. This review mainly deals with the efforts of the authers group towards the design of non-thiol-farnesyltransferase inhibitors. Our first step on the way to non-thiol farnesyltransferase inhibitors was the development of an CAAX-peptidomimetic based on a pharmacophore model. On the basis of this benzophenone core, bisubstrate analogues were developed as one class of non-thiol farnesyltransferase inhibitors. In most non-thiol farnesyltransferase inhibitors known in literature nitrogene containing heterocycles are used as cysteine replacements supposedly coordinating the enzyme bound zinc. However, we and others have shown that nitrogen heterocycles can be replaced by aryl residues lacking the ability to coordinate metal atoms, an observation which let to the postulation of two hitherto unknown aryl binding sites. Using flexible docking of model compounds and GRID analysis we were able to locate these postulated aryl binding sites. Subsequently, we used one of this aryl binding sites for the structure based design of highly active non-thiol farnesyltransferase inhibitors.
Insights
Researchers designed novel non-thiol farnesyltransferase inhibitors for cancer therapy. By identifying new aryl binding sites, they developed highly active compounds, avoiding adverse effects linked to thiol-based inhibitors.
Area of Science:
- Medicinal Chemistry
- Drug Discovery
- Biochemistry
Background:
- Farnesyltransferase (FTase) is a key target for anti-cancer drug development.
- Current FTase inhibitors often contain thiols, leading to adverse effects.
- Non-thiol FTase inhibitors are sought to improve drug safety and efficacy.
Purpose of the Study:
- To design and develop novel non-thiol farnesyltransferase inhibitors.
- To explore alternative structural motifs for FTase inhibition.
- To identify and utilize novel binding sites within the farnesyltransferase enzyme.
Main Methods:
- Development of CAAX-peptidomimetics based on a pharmacophore model.
- Design of bisubstrate analogues as non-thiol FTase inhibitors.
- Utilizing flexible docking and GRID analysis to identify aryl binding sites.
- Structure-based design of inhibitors targeting identified aryl binding sites.
Main Results:
- Successful design of non-thiol farnesyltransferase inhibitors.
- Identification of two novel aryl binding sites within the enzyme.
- Demonstration that nitrogen heterocycles can be replaced by aryl residues.
- Development of highly active non-thiol FTase inhibitors based on structure-guided design.
Conclusions:
- Novel non-thiol farnesyltransferase inhibitors were successfully designed and synthesized.
- The identification of new aryl binding sites offers new avenues for inhibitor design.
- Structure-based design utilizing these sites leads to highly potent compounds.
- This approach holds promise for developing safer and more effective anti-cancer drugs.