8OKU
Salt-Inducible Kinase 3 in complex with an inhibitor
Summary for 8OKU
| Entry DOI | 10.2210/pdb8oku/pdb |
| Descriptor | Serine/threonine-protein kinase SIK3, ~{N}-ethyl-4-[5-[1-(2-hydroxyethyl)pyrazol-4-yl]benzimidazol-1-yl]-2,6-dimethoxy-benzamide (3 entities in total) |
| Functional Keywords | kinase uba inhibitor, signaling protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 81671.01 |
| Authors | Flower, T.G.,Leonard, P.M.,Lamers, M.B.A.C.,Mollat, P. (deposition date: 2023-03-29, release date: 2024-01-10, Last modification date: 2024-01-24) |
| Primary citation | Temal-Laib, T.,Peixoto, C.,Desroy, N.,De Lemos, E.,Bonnaterre, F.,Bienvenu, N.,Picolet, O.,Sartori, E.,Bucher, D.,Lopez-Ramos, M.,Roca Magadan, C.,Laenen, W.,Flower, T.,Mollat, P.,Bugaud, O.,Touitou, R.,Pereira Fernandes, A.,Lavazais, S.,Monjardet, A.,Borgonovi, M.,Gosmini, R.,Brys, R.,Amantini, D.,De Vos, S.,Andrews, M. Optimization of Selectivity and Pharmacokinetic Properties of Salt-Inducible Kinase Inhibitors that Led to the Discovery of Pan-SIK Inhibitor GLPG3312. J.Med.Chem., 67:380-401, 2024 Cited by PubMed Abstract: Salt-inducible kinases (SIKs) SIK1, SIK2, and SIK3 are serine/threonine kinases and form a subfamily of the protein kinase AMP-activated protein kinase (AMPK) family. Inhibition of SIKs in stimulated innate immune cells and mouse models has been associated with a dual mechanism of action consisting of a reduction of pro-inflammatory cytokines and an increase of immunoregulatory cytokine production, suggesting a therapeutic potential for inflammatory diseases. Following a high-throughput screening campaign, subsequent hit to lead optimization through synthesis, structure-activity relationship, kinome selectivity, and pharmacokinetic investigations led to the discovery of clinical candidate GLPG3312 (compound ), a potent and selective pan-SIK inhibitor (IC: 2.0 nM for SIK1, 0.7 nM for SIK2, and 0.6 nM for SIK3). Characterization of the first human SIK3 crystal structure provided an understanding of the binding mode and kinome selectivity of the chemical series. GLPG3312 demonstrated both anti-inflammatory and immunoregulatory activities in human primary myeloid cells and in mouse models. PubMed: 38147525DOI: 10.1021/acs.jmedchem.3c01428 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.1 Å) |
Structure validation
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