I N D U S T R I A L R E S E A R C H

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PRINCIPAL PUBLICATION AND AUTHORS

Rational Design of Highly Potent, Selective, and Bioavailable SGK1 Protein Kinase Inhibitors for the Treatment of Osteoarthritis, N. Halland (a), F. Schmidt (a), T. Weiss (a), Z. Li (a), J. Czech (a), J. Saas (a), D. Ding-Pfennigdorff (a), M.K. Dreyer (a), C. Strübing (a), M. Nazare (b), J. Med. Chem. 65, 2, 1567-1584 (2022); https:/doi.org/10.1021/acs.jmedchem.1c01601 (a) Integrated Drug Discovery, Sanofi R&D, Frankfurt am Main (Germany) (b) Leibniz-Institut für Molekulare Pharmakologie (FMP), Berlin-Buch (Germany)

Fig. 140: X-ray co-crystal structure of human serum and glucocorticoid-regulated kinase 1 (hSGK1) in complex with pyrazolopyridine inhibitor 3a (Protein Data Bank entry 7PUE).

Rational design of SGK1 protein kinase inhibitors for the treatment of osteoarthritis

The rational design of a highly selective druglike SGK1 inhibitor was facilitated by a novel hSGK1 co-crystal structure identified using synchrotron X-ray crystallography. The crystal structure shows a highly optimised profile suitable for oral dosing as a novel, potentially disease-modifying agent for osteoarthritis.

The serine/threonine kinase SGK1 is expressed in many tissues, but it is found to be upregulated in diseased osteoarthritic cartilage. SGK1 acts as an activator of the β-catenin pathway and consequently as a stimulator of cartilage degradation. Given the high prevalence of this chronic disease, oral disease-modifying treatments are needed but are facing high requirements for the drug selectivity, pharmacokinetic and safety profiles. An earlier lead series based on [4-(1H-pyrazolo[3,4-b]pyrazin-6-yl) phenyl]-sulfonamides provided good starting points but did not match the safety profile requirements.

A rational, multiparameter optimisation strategy was followed, supported by X-ray crystallography and modelling, to arrive at highly potent, bioavailable 1H-pyrazolo[3,4-d] pyrimidines with an improved safety profile. Rational compound design was facilitated by a novel hSGK1 co- crystal structure, while multiple ligand-based computer models were applied to guide the chemical optimisation of the compound ADMET and selectivity profiles.

The single site mutant protein SGK1-60-431R192A-S422D was crystallised to optimise resolution. Data were collected at beamline ID29 and the coordinates were deposited in the Protein Data Bank as entry 7PUE (Figure 140). The compound faces the hinge segment in the binding pocket with the pyrazole ring, the pyrrolidine ring points towards the solvent, and the dichlorophenyl moiety binds to the hydrophobic pocket at Leu162. The DFG-loop wraps around the sulfonyl group, resulting in a conformation not yet seen in SGK1. The dichlorophenyl group occupies the space that is taken by Phe241 in the DFG-up conformers. Compounds underwent subchronic proof-of-mechanism studies, allowing to identify a druglike SGK1 inhibitor with a highly optimised profile, suitable for oral dosing in the indication.