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Rational approach to highly potent and selective apoptosis signal-regulating kinase 1 (ASK1) inhibitors
Frank Lovering1, Paul Morgan2, Christophe Allais3
1Medicine Design, Pfizer, Inc., 1 Portland Street, Cambridge, MA 02139, USA.
Abstract:
Many diseases are believed to be driven by pathological levels of reactive oxygen species (ROS) and oxidative stress has long been recognized as a driver for inflammatory disorders. Apoptosis signal-regulating kinase 1 (ASK1) has been reported to be activated by intracellular ROS and its inhibition leads to a down regulation of p38-and JNK-dependent signaling. Consequently, ASK1 inhibitors may have the potential to treat clinically important inflammatory pathologies including renal, pulmonary and liver diseases. Analysis of the ASK1 ATP-binding site suggested that Gln756, an amino acid that rarely occurs at the GK+2 position, offered opportunities for achieving kinase selectivity for ASK1 which was applied to the design of a parallel medicinal chemistry library that afforded inhibitors of ASK1 with nanomolar potency and excellent kinome selectivity. A focused optimization strategy utilizing structure-based design resulted in the identification of ASK1 inhibitors with low nanomolar potency in a cellular assay, high selectivity when tested against kinase and broad pharmacology screening panels, and attractive physicochemical properties. The compounds we describe are attractive tool compounds to inform the therapeutic potential of ASK1 inhibition.
Insights
Researchers developed novel inhibitors targeting Apoptosis Signal-Regulating Kinase 1 (ASK1), a key enzyme in oxidative stress and inflammation. These potent and selective compounds offer potential for treating inflammatory diseases like kidney, lung, and liver conditions.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Molecular Biology
Background:
- Reactive oxygen species (ROS) and oxidative stress are implicated in numerous diseases, particularly inflammatory disorders.
- Apoptosis Signal-Regulating Kinase 1 (ASK1) is activated by intracellular ROS and mediates inflammatory signaling pathways (p38 and JNK).
- Inhibition of ASK1 presents a therapeutic strategy for inflammatory conditions affecting organs such as the kidney, lungs, and liver.
Purpose of the Study:
- To design and identify novel, potent, and selective inhibitors of ASK1.
- To leverage specific amino acid residues within the ASK1 ATP-binding site for kinase selectivity.
- To develop tool compounds for investigating the therapeutic potential of ASK1 inhibition in inflammatory diseases.
Main Methods:
- Structure-based drug design utilizing the ASK1 ATP-binding site, focusing on Gln756.
- Creation of a parallel medicinal chemistry library to generate ASK1 inhibitors.
- Focused optimization and structure-activity relationship studies.
- In vitro biochemical and cellular assays to assess potency and selectivity.
- Kinome and broad pharmacology screening panels to evaluate off-target effects.
Main Results:
- Identification of ASK1 inhibitors with nanomolar potency from the initial library.
- Achieved excellent kinome selectivity by targeting unique features of the ASK1 ATP-binding site.
- Optimized compounds demonstrated low nanomolar potency in cellular assays.
- Selected inhibitors exhibited high selectivity across kinase and broad pharmacology panels.
- Developed compounds possessed favorable physicochemical properties for further development.
Conclusions:
- Novel ASK1 inhibitors with high potency and selectivity were successfully developed.
- The targeted design strategy, focusing on Gln756, proved effective for achieving selectivity.
- These compounds serve as valuable tools for exploring the therapeutic benefits of ASK1 inhibition.
- The findings support the potential of ASK1 inhibitors in treating various inflammatory diseases.
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