8OKU

Salt-Inducible Kinase 3 in complex with an inhibitor

8OKU の概要

• エントリーDOI: 10.2210/pdb8oku/pdb
• 分子名称: 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)
• 機能のキーワード: kinase uba inhibitor, signaling protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 81671.01

構造登録者

Flower, T.G.,Leonard, P.M.,Lamers, M.B.A.C.,Mollat, P. (登録日: 2023-03-29, 公開日: 2024-01-10, 最終更新日: 2024-01-24)

主引用文献

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

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: 38147525
DOI: 10.1021/acs.jmedchem.3c01428

実験手法

X-RAY DIFFRACTION (3.1 Å)