Research Progress of Discoid Domain Receptor 1 (DDR1) Inhibitors

Discoid domain receptor 1 (DDR1) is a collagen-activated receptor tyrosine kinase that plays a key role in regulating important processes, such as cell differentiation, proliferation, adhesion, migration, invasion and matrix remodeling.Overexpression or activation of DDR1 is closely related to the occurrence and development of inflammation, as well as tumor invasion and metastasis.Therefore, DDR1 is a potential target for the treatment of diseases, such as inflammation, fibrosis and malignancy.Since the early 1990s, a variety of DDR1 small molecule inhibitors have been reported successively.This article focuses on the structure, function, mechanism and signaling pathways of DDR1, and the design, structure-activity relationship and pharmacological activity of DDR1 small molecule inhibitors from the perspective of medicinal chemistry are reviewed.Keywords discoid domain receptor 1 (DDR1); inhibitor; collagen 1 DDR1 背景简介 盘状结构域受体(discoidin domain receptors, DDRs) 是 20 世纪 90 年代初发现的跨膜受体酪氨酸激酶 (receptor tyrosine kinase, RTKs)超家族的成员, 与其他 RTKs 在结构上的区别在于, 胞外区存在盘状蛋白基序, 是一种新型胶原激活的 RTK.DDRs 家族包括 DDR1 和 DDR2 两个亚型, DDR1 (DDR1a, DDR1b, DDR1c, DDR-1d 和 DDR1e)的五种剪切异构体在糖基化程度、蛋白质 相互作用、 表达模式、 磷酸化及活性均有不同, 而 DDR2 只有一种结构 [1] .细胞外基质(extracellular matrix, ECM) 在维持组织的各种物理化学、结构和生理特性方面起着 重要作用, 其失调可能导致异常的细胞行为, 促进恶性 肿瘤形成.三螺旋胶原是 ECM 中含量最丰富的成分, 常见的 RTKs 一般以肽样生长因子作为配体, 而 DDRs 则被各种类型的三螺旋胶原激活.研究表明 DDR1 和