Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, Moscow, Russian Federation, 119991.
National Research University Higher School of Economics (HSE), 20 Myasnitskaya Street, Moscow, Russian Federation, 101000.
Sci Rep. 2021 Nov 30;11(1):23120. doi: 10.1038/s41598-021-02568-6.
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 IC 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.
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，一种有效的疾病修饰治疗方法应该同时作用于这两个致病成分。已知 cSrc 激酶参与骨和软骨重塑，而 SYK 激酶与炎症成分有关。因此，本研究的目的是在不同的体外和体内关节炎模型中，研究一种针对 SYK 和 cSrc 激酶等多种激酶的小分子多激酶抑制剂 MT-SYK-03 的作用机制和疗效。用 341 种激酶的试剂盒检测 MT-SYK-03 激酶抑制的选择性。该化合物在一组 OA 的体外模型和体内 OA 和 RA 模型中进行了评估：手术诱导性关节炎（SIA）、单碘乙酸诱导性关节炎（MIA）、胶原诱导性关节炎（CIA）、佐剂诱导性关节炎（AIA）。MT-SYK-03 对 cSrc 和 SYK 的抑制 IC 分别为 14.2 和 23 nM。只有 5 种激酶在 500 nM 的 MT-SYK-03 下被抑制超过 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。MT-SYK-03 在大鼠中优先分布于关节和骨组织，并在体内显示出疾病修饰活性，在大鼠 SIA 模型中使软骨侵蚀深度减半，并在大鼠 MIA 模型中提高疼痛阈值。在单药治疗方案和与甲氨蝶呤（MTX）联合治疗小鼠和大鼠 CIA 模型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 疾病修饰治疗的可行策略。MT-SYK-03 的 2 期临床研究即将开始。
