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Updated: Oct 9, 2025
Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
Published on: October 23, 2019
Rational Design of Highly Potent, Selective, and Bioavailable SGK1 Protein Kinase Inhibitors for the Treatment of
Nis Halland1, Friedemann Schmidt1, Tilo Weiss1
1Integrated Drug Discovery, Sanofi R&D, Industriepark Höchst, D-65926 Frankfurt am Main, Germany.
Abstract:
The serine/threonine kinase SGK1 is an activator of the β-catenin pathway and a powerful stimulator of cartilage degradation that is found to be upregulated under genomic control in diseased osteoarthritic cartilage. Today, no oral disease-modifying treatments are available and chronic treatment in this indication sets high requirements for the drug selectivity, pharmacokinetic, and safety profile. We describe the identification of a highly selective druglike 1H-pyrazolo[3,4-d]pyrimidine SGK1 inhibitor 17a that matches both safety and pharmacokinetic requirements for oral dosing. Rational compound design was facilitated by a novel hSGK1 co-crystal structure, and multiple ligand-based computer models were applied to guide the chemical optimization of the compound ADMET and selectivity profiles. Compounds were selected for subchronic proof of mechanism studies in the mouse femoral head cartilage explant model, and compound 17a emerged as a druglike SGK1 inhibitor, with a highly optimized profile suitable for oral dosing as a novel, potentially disease-modifying agent for osteoarthritis.
Insights
Researchers identified a novel, selective SGK1 inhibitor (17a) for osteoarthritis. This druglike compound shows promise as an oral disease-modifying treatment, meeting safety and pharmacokinetic requirements.
Area of Science:
- Biochemistry
- Pharmacology
- Osteoarthritis Research
Background:
- Osteoarthritis (OA) involves cartilage degradation, partly driven by upregulated serine/threonine kinase SGK1.
- Currently, no oral disease-modifying OA treatments exist, necessitating drugs with high selectivity and favorable pharmacokinetic/safety profiles.
Purpose of the Study:
- To identify and develop a selective, orally available SGK1 inhibitor for osteoarthritis treatment.
- To optimize compound properties for safety, pharmacokinetics, and efficacy.
Main Methods:
- Utilized a novel human SGK1 co-crystal structure for rational drug design.
- Employed multiple ligand-based computational models to guide chemical optimization.
- Evaluated compound ADMET and selectivity profiles.
- Conducted subchronic proof-of-mechanism studies in a mouse femoral head cartilage explant model.
Main Results:
- Identified a highly selective 1H-pyrazolo[3,4-d]pyrimidine SGK1 inhibitor, designated 17a.
- Compound 17a demonstrated druglike properties and optimized safety and pharmacokinetic profiles suitable for oral administration.
- The inhibitor showed potential as a disease-modifying agent in OA models.
Conclusions:
- Compound 17a represents a promising, orally bioavailable SGK1 inhibitor for osteoarthritis.
- The developed compound addresses the unmet need for disease-modifying OA treatments.
- Further development of 17a could lead to a novel therapeutic strategy for osteoarthritis.
