Inhibition of SYK and cSrc kinases can protect bone and cartilage in preclinical models of osteoarthritis and rheumatoid arthritis.
Inhibition of SYK and cSrc kinases can protect bone and cartilage in preclinical models of osteoarthritis and rheumatoid arthritis.
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DOI：
10.1038/s41598-021-02568-6
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发表时间：
2021-11-30
影响因子：
4.6
通讯作者：
Chilov GG
中科院分区：
文献类型：
--
作者：
Novikov FN;Panova MV;Titov IY;Stroylov VS;Stroganov OV;Chilov GG
骨关节炎（OA）的病理生理学包括软骨下骨组织的破坏和滑膜的炎症。因此，有效的疾病改善治疗应该作用于这两种致病成分。已知cSrc激酶参与骨和软骨重塑，SYK激酶与炎症组分相关。因此，本研究的目的是表征靶向SYK和cSrc激酶等的小分子多激酶抑制剂MT-SYK-03在不同的体外和体内关节炎模型中的作用机制和功效。在一组341种激酶上测定MT-SYK-03激酶抑制的选择性。在一组OA的体外模型和体内OA和RA模型中评价了该化合物：药物诱导的关节炎（SIA）、碘乙酸诱导的关节炎（MIA）、胶原诱导的关节炎（CIA）、类固醇诱导的关节炎（AIA）。MT-SYK-03抑制cSrc和SYK，IC 50分别为14.2和23 nM。在500 nM的MT-SYK-03下，仅5种激酶被抑制> 90%。在体外OA模型中，MT-SYK-03减少软骨细胞的肥大变化、骨吸收，并抑制SYK介导的炎症信号传导。MT-SYK-03显示出优先分布到关节和骨组织（在大鼠中），并通过使大鼠SIA模型中的软骨侵蚀深度减半和增加大鼠MIA模型中的疼痛阈值而显示出体内疾病改善活性。在小鼠和大鼠CIA模型中，在单药治疗方案和与甲氨蝶呤（MTX）联合治疗中显示出软骨保护和抗吸收作用;在大鼠AIA模型中，免疫介导的炎症减少。获得的临床前数据支持抑制cSrc和SYK作为OA疾病改善治疗的可行策略。即将开始MT-SYK-03的II期临床研究。
The pathophysiology of osteoarthritis (OA) includes the destruction of subchondral bone tissue and inflammation of the synovium. Thus, an effective disease-modifying treatment should act on both of these pathogenetic components. It is known that cSrc kinase is involved in bone and cartilage remodeling, and SYK kinase is associated with the inflammatory component. Thus the aim of this study was to characterize the mechanism of action and efficacy of a small molecule multikinase inhibitor MT-SYK-03 targeting SYK and cSrc kinases among others in different in vitro and in vivo arthritis models. The selectivity of MT-SYK-03 kinase inhibition was assayed on a panel of 341 kinases. The compound was evaluated in a set of in vitro models of OA and in vivo OA and RA models: surgically-induced arthritis (SIA), monosodium iodoacetate-induced arthritis (MIA), collagen-induced arthritis (CIA), adjuvant-induced arthritis (AIA). MT-SYK-03 inhibited cSrc and SYK with IC50 of 14.2 and 23 nM respectively. Only five kinases were inhibited > 90% at 500 nM of MT-SYK-03. In in vitro OA models MT-SYK-03 reduced hypertrophic changes of chondrocytes, bone resorption, and inhibited SYK-mediated inflammatory signaling. MT-SYK-03 showed preferential distribution to joint and bone tissue (in rats) and revealed disease-modifying activity in vivo by halving the depth of cartilage erosion in rat SIA model, and increasing the pain threshold in rat MIA model. Chondroprotective and antiresorptive effects were shown in a monotherapy regime and in combination with methotrexate (MTX) in murine and rat CIA models; an immune-mediated inflammation in rat AIA model was decreased. The obtained preclinical data support inhibition of cSrc and SYK as a viable strategy for disease-modifying treatment of OA. A Phase 2 clinical study of MT-SYK-03 is to be started.
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影响因子：
3.7
作者：
Han, Tianzhen;Mignatti, Paolo;Attur, Mukundan
通讯作者：
Attur, Mukundan
骨关节炎和骨质疏松症患者的关节软骨退化和异常软骨下骨重塑。
影响因子：
6.2
作者：
Chu, Linyang;Liu, Xuqiang;Yu, Zhifeng
通讯作者：
Yu, Zhifeng
影响因子：
--
作者：
Holanda, Haroldo Tenório de;Pollak, Daniel Feldman;Pucinelli, Mário Luis Cardoso
通讯作者：
Pucinelli, Mário Luis Cardoso
DOI：
10.1124/jpet.106.109058
发表时间：
2006-12-01
影响因子：
3.5
作者：
Braselmann, Sylvia;Taylor, Vanessa;Masuda, Esteban S.
通讯作者：
Masuda, Esteban S.
影响因子：
7
作者：
Gerwin, N.;Bendele, A. M.;Carlson, C. S.
通讯作者：
Carlson, C. S.