Rational Design of Highly Potent, Selective, and Bioavailable SGK1 Protein Kinase Inhibitors for the Treatment of Osteoarthritis

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 diseasemodifying 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 ligandbased 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.

AGC Kinase Inhibitors Regulate STING Signaling Through SGK-Dependent and SGK-Independent Mechanisms

“…The ability of Sanofi-14h treatment to inhibit activation of TBK1 led us to examine a panel of SGK and AGC family kinase inhibitors for their effects on STING-induced signaling. In this regard, we synthesized Sanofi 17a 31 , a derivative of Sanofi-14h, which preferentially targets SGK1 (Fig. 5A) 31 .…”

“…In this regard, we synthesized Sanofi 17a 31 , a derivative of Sanofi-14h, which preferentially targets SGK1 (Fig. 5A) 31 . We found that Sanofi-14h, Sanofi-17a, GSK650394, and SI113 all inhibited STING-driven IRF3 activation in a reporter assay with similar potency.…”

“…Sanofi-14h is preferential for SGK3 and Sanofi-17a is preferential for SGK1, underscoring the potential importance of SGK subtype preference for these inhibitors related to different biological effects and expression. These studies showed that other kinases are targeted by these inhibitors, as Sanofi-14h was shown to have significant activity against S6K1 and MLK3 23,31 . Our studies revealed an unexpected effect of Sanofi-14h on inhibition of IFNb mRNA induction following treatment of macrophages cells with the STING agonist DMXAA (Fig.…”

“…Using an IRF3-dependent luciferase reporter system in RAW264.7 macrophages (Invivogen), we tested DMXAA-stimulated cells pre-treated with 5 different SGK inhibitors across a 10,000-fold concentration range. For this study we synthesized and tested Sanofi-17a, a structural derivative of Sanofi-14h, that was recently described 31 and which preferentially targets SGK1 over SGK3. We included three other small molecules, namely GSK650394, SI113, and EMD638683, with established SGK inhibitory activity [27][28][29] .…”

“…The lack of effect on TBK1 phosphorylation, IFN expression, or STING-TBK1 interaction by Akt or P70S6K inhibitors makes it unlikely that Sanofi-14h affects the TBK1/IFN pathway via those kinases (see Discussion). to block induced SGK activity associated with Akt inhibition in breast cancer, and Halland et al 23,31 developed Sanofi-17a to target SGK in an osteoarthritis model. Sanofi-14h is preferential for SGK3 and Sanofi-17a is preferential for SGK1, underscoring the potential importance of SGK subtype preference for these inhibitors related to different biological effects and expression.…”