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Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor
Published on: September 13, 2018
Discovery and Optimization of LATS1 and LATS2 Kinase Inhibitors for Use in Regenerative Medicine
Patrick J Morris1, Damien Y Duveau1, Michele Ceribelli1
1Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850, United States.
Abstract:
The Large Tumor Suppressor Kinases 1 and 2 (LATS1/2) are serine/threonine kinases that play an essential role in Hippo pathway activation and influence multiple physiological events ranging from organ growth to tissue regeneration. As a result, pharmacological inhibition of LATS1/2 represents a promising strategy for therapeutic intervention in multiple indications. Within, we present the discovery of potent and selective inhibitors of the kinases LATS1 and LATS2. Using a scaffold hopping strategy from the reported AKT inhibitor AT-7867 (1) we pursued a series of structure activity relationship (SAR) studies that dramatically improved potency versus LATS1 and LATS2, while concurrently improving kinome-wide selectivity. ADME properties were further optimized via introduction of conformational restriction into the target molecule, to lead to compound 27 which possesses potent inhibitory activity against both LATS1 and LATS2 and proof of concept activity in wound healing models.
Insights
Researchers discovered potent and selective inhibitors for Large Tumor Suppressor Kinases 1 and 2 (LATS1/2). These compounds show promise for therapeutic applications and demonstrated efficacy in wound healing models.
Area of Science:
- Biochemistry
- Pharmacology
- Molecular Biology
Background:
- Large Tumor Suppressor Kinases 1 and 2 (LATS1/2) are key regulators of the Hippo pathway.
- LATS1/2 activity is crucial for organ growth, tissue regeneration, and cellular homeostasis.
- Dysregulation of LATS1/2 is implicated in various diseases, making them attractive therapeutic targets.
Purpose of the Study:
- To discover and develop novel, potent, and selective small-molecule inhibitors of LATS1 and LATS2.
- To optimize identified inhibitors for improved pharmacological properties and in vivo efficacy.
Main Methods:
- Utilized a scaffold hopping approach starting from an AKT inhibitor (AT-7867).
- Conducted extensive structure-activity relationship (SAR) studies to enhance potency and selectivity.
- Optimized ADME properties through conformational restriction strategies.
Main Results:
- Identified compound 27 as a potent and selective inhibitor of both LATS1 and LATS2.
- Achieved significant improvements in kinome-wide selectivity compared to the starting scaffold.
- Demonstrated proof-of-concept activity of compound 27 in preclinical wound healing models.
Conclusions:
- Successfully discovered novel LATS1/2 inhibitors with excellent potency and selectivity.
- Compound 27 represents a promising therapeutic candidate for indications involving LATS1/2 modulation.
- The developed inhibitors warrant further investigation for their clinical potential in regenerative medicine and other therapeutic areas.
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