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Allosteric Regulation

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Allosteric regulation of enzymes occurs when the binding of an effector molecule to a site that is different from the active site causes a change in the enzymatic activity. This alternate site is called an allosteric site, and an enzyme can contain more than one of these sites. Allosteric regulation can either be positive or negative, resulting in an increase or decrease in enzyme activity. Most enzymes that display allosteric regulation are metabolic enzymes involved in the degradation or...

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Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays

Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays

Published on: October 23, 2019

Covalent-Allosteric Kinase Inhibitors.

Jörn Weisner¹, Rajesh Gontla¹, Leandi van der Westhuizen²

¹Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie, Otto-Hahn-Strasse 6, 44227 Dortmund (Germany).

Angewandte Chemie (International Ed. in English)

|June 26, 2015

Summary

Researchers developed novel covalent-allosteric inhibitors (CAIs) that target specific conformations of the Akt kinase. These potent and selective modulators stabilize the inactive kinase state, offering a new tool for chemical biology and medicinal chemistry.

Keywords:

cancer drug design inter-domain interactions medicinal chemistry tumor thermapeutics

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Area of Science:

Biochemistry
Molecular Biology
Medicinal Chemistry

Background:

Protein kinases play crucial roles in cell signaling.
Targeting specific kinase conformations is key to understanding and modulating signaling pathways.
The Akt kinase is a significant target in various diseases.

Purpose of the Study:

To design and synthesize novel covalent-allosteric inhibitors (CAIs) targeting the Akt kinase.
To stabilize the inactive conformation of the Akt kinase using structure-based design.
To evaluate the potency and selectivity of these novel CAIs.

Main Methods:

Structure-based drug design was employed.
Synthesis of pleckstrin homology (PH) domain-dependent CAIs.
Biochemical assays to evaluate inhibitor potency and selectivity against Akt kinase.

Main Results:

Novel CAIs were successfully designed and synthesized.
These inhibitors covalently bind to a specific cysteine residue on the Akt kinase.
The inhibitors effectively stabilize the inactive conformation of Akt.
High potency and selectivity were observed for the developed modulators.

Conclusions:

The developed CAIs represent an innovative approach for targeting kinase conformations.
These inhibitors provide valuable chemical probes for studying Akt signaling.
The findings open new avenues for medicinal chemistry research and drug development targeting kinases.