Rational design of highly potent, selective, and bioavailable SGK1 protein kinase inhibitors for the treatment of osteoarthritis

Item Type:	Article
Title:	Rational design of highly potent, selective, and bioavailable SGK1 protein kinase inhibitors for the treatment of osteoarthritis
Creators Name:	Halland, N. and Schmidt, F. and Weiss, T. and Li, Z. and Czech, J. and Saas, J. and Ding-Pfennigdorff, D. and Dreyer, M.K. and Strübing, C. and Nazare, M.
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 1(H)-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.
Keywords:	Rodent Models, Inhibitors, Inhibition, Peptides and Proteins, Selectivity, Animals, Mice, Rats
Source:	Journal of Medicinal Chemistry
ISSN:	0022-2623
Publisher:	American Chemical Society
Volume:	65
Number:	2
Page Range:	1567-1584
Date:	27 January 2022
Official Publication:	https://doi.org/10.1021/acs.jmedchem.1c01601
PubMed:	View item in PubMed

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