CDK6和DYRK2双靶点抑制剂抗骨髓瘤活性的结构优化及作用机制研究

多发性骨髓瘤（MM）发病率高且不可治愈，急需新型药物。针对单一靶向周期蛋白依赖性激酶6(CDK6)或者双特异性酪氨酸磷酸化调节激酶2（DYRK2）的化合物活性不理想、易产生耐药等缺点，申请人利用反向计算化学基因组学技术，通过分析蛋白结构和创新设计，发现并合成了具有自主知识产权、靶向CDK6和DYRK2双靶点的全新喹喔啉化合物PY-612，其对双靶点活性均达到nM级别，体内外显示出很好的抗MM活性。.本项目拟在此原创性工作基础上，以PY-612为先导物，抑制双靶点为活性导向，开展较为系统的结构优化，阐明构效关系，并通过安全性、药代以及体内药效等综合性评价，获得治疗窗口宽、成药性好的新型双靶点抗MM候选物。同时，以PY-612为探针，探明此类化合物如何通过双靶点产生协同抗癌作用，解析通过怎样的信号通路发挥抗MM作用，为发展成为一类新型抗MM候选药物，提供充足的理论基础以及全新的治疗策略。

Multiple Myeloma (MM) is the second most common malignant tumor in the hematological system. It has a high incidence and is incurable. Current single-target drugs have low efficiency and high toxicity, so it is urgent to study new drugs with unique mechanism for the treatment of multiple myeloma patients. Cyclin-dependent kinase 6 (CDK6) and dual-specificity tyrosine-regulated kinase 2 (DYRK2) play important regulatory roles in MM cells and are promising targets for anti-cancer drugs. However, compounds targeting CDK6 or DYRK2 in the literature showed moderate anti-MM activity. In recent years, the applicant has been engaged in the research of drugs targeted on CDK6 and DYRK2. Using the technique of reverse computational chemical genomics to analyze the crystal structures of these two proteins, we creatively designed, synthesized and discovered lead compound PY-612. The novel compound PY-612 has nM-level activity against both CDK6 and DYRK2 targets, and also has good anti-MM effects in vitro and in vivo. .Based on these promising results, this project will be focused on discovery of new lead compounds, structure optimization, and bioactivity evaluation, in order to obtain novel CDK6 and DYRK2 double-target inhibitors with high activity, selectivity and good drug-like property, and to provide new drug candidates for the treatment of tumors such as MM. Taking PY-612 as the probe, we will also conduct mechanism studies to clarify how these compounds produce synergistic anti-MM effect through double targets, and to provide sufficient theoretical basis and new treatment strategies for developing a new type of anti-MM candidate drugs.