选择性盘状结构域受体（DDRs）小分子抑制剂的设计、合成及生物活性研究

The discoidin domain receptors (DDRs) are a unique class of transmembrane receptor tyrosine kinases. Two isoforms of DDRs, i.e. DDR1 and DDR2, have been identified with distinct expression profiles and ligand specificities. DDRs play crucial roles in the regulation of fundamental cellular processes, such as proliferation, survival, differentiation, adhesion, and matrix remodeling. Dysregulation of DDRs has been linked to many human diseases, including different types of cancer and inflammation related disorders such as fibrotic disorders, atherosclerosis and arthritis. Thus, DDRs have been considered as emerging potential molecular targets for new drug discovery. Several small molecule Bcr-Abl inhibitors, imatinib, nilotinib, dasatinib, bafetinib and ponatinib, were reported to potently suppress the kinase activity of DDR1 and DDR2. However, the low selectivity of these molecules limits their potential as tools for the validation of DDRs as drug targets. It is highly desirable to identify selective DDR inhibitors as chemical probes to further validate DDR1 and DDR2 as drug targets..We have successfully designed and synthesized a series of 3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl) ethynyl)benzamides that are selective DDR1 inhibitors. One of the most promising compound 12 tightly binds with DDR1 with Kd value of 0.6 nM and inhibits its enzymatic activity of DDR1 with IC50 values of 6.8 nM, but is significantly less potent against other kinases in a profiling study on a panel of 455 different kinases. On the basis of previous investigation, we will continue our SAR research of compound 12, and will design and synthsis of new generation of DDR1 or DDR2 inhibitors using rational drug design strategys. Besides, we will also investigate the potential application of DDRs ihibitors for the treatment of inflammation and its related diseases such as lung fibrosis.

盘状结构域受体激酶（DDRs）的过度表达或激活与炎症发生、发展以及肿瘤细胞侵袭、转移等病理过程密切相关，是开发治疗纤维化、动脉粥样硬化、关节炎等炎症相关疾病及恶性肿瘤的潜在新靶标。但目前报道的小分子抑制剂存在选择性较差或活性较弱的缺陷，迫切需要高选择性的DDRs小分子抑制剂作为工具来研究其作为药物开发靶标的可能性。最近，我们通过分析DDR1 激酶ATP结合域的结构特征，成功设计和合成了全新小分子抑制剂12，可以以0.6 nM亲和力(Kd值)与DDR1 结合并抑制其激酶活性（IC50为6.8 nM），而在较高浓度下对其它455种激酶不产生明显影响。是目前报道的选择性最好的DDR1小分子抑制剂之一。本项目拟在前期基础上系统研究先导分子的构效关系，并设计全新骨架的DDR1或DDR2小分子抑制剂，研究化合物的抗炎活性及其在肺纤维化等疾病中的治疗效果。为进一步验证其作为药物开发靶标奠定基础。

盘状结构域受体激酶（DDRs）的过度表达或激活与炎症发生、发展以及肿瘤细胞侵袭、转移等病理过程密切相关，是开发治疗纤维化、动脉粥样硬化、关节炎等炎症相关疾病及恶性肿瘤的潜在新靶标。但目前报道的小分子抑制剂存在选择性较差或活性较弱的缺陷，迫切需要高选择性的DDRs小分子抑制剂作为工具来研究其作为药物开发靶标的可能性。.我们通过分析DDR1激酶ATP结合域的结构特征，成功设计和合成了全新小分子抑制剂12，可以以0.6nM亲和力(Kd值)与DDR1 结合并抑制其激酶活性（IC50为6.8nM），而在较高浓度下对其它455种激酶不产生明显影响。是目前报道的选择性最好的DDR1小分子抑制剂之一。本项目拟在前期基础上系统研究先导分子的构效关系，并设计项目总计合成三大类的全新结构抑制剂，总计约300余个化合物。通过进一步的生物学研究获得作为抗急性肺损伤和肺纤维化先导化合物3个。.基于这些研究，发表相关的SCI论文11篇，申请发明专利4项，获授权专利 2项，培养硕士研究生4名，博士研究生3名。