Abstract：
Lysine demethylase 5 (KDM5) proteins are involved in various neurological disorders, including Alzheimer\'s disease, and KDM5 inhibition is expected to be a therapeutic strategy for these diseases. However, the pharmacological effects of conventional KDM5 inhibitors are insufficient, as they only target the catalytic functionality of KDM5. To identify compounds that exhibit more potent pharmacological activity, we focused on proteolysis targeting chimeras (PROTACs), which degrade target proteins and thus inhibit their entire functionality. We designed and synthesized novel KDM5 PROTAC candidates based on previously identified KDM5 inhibitors. The results of cellular assays revealed that two compounds, 20b and 23b, exhibited significant neurite outgrowth-promoting activity through the degradation of KDM5A in neuroblastoma neuro 2a cells. These results suggest that KDM5 PROTACs are promising drug candidates for the treatment of neurological disorders.
摘要：
赖氨酸脱甲基酶5（KDM5）蛋白参与各种神经系统疾病，包括老年痴呆症,和KDM5抑制有望成为这些疾病的治疗策略。然而,常规KDM5抑制剂的药理作用不足，因为它们仅针对KDM5的催化功能。为了确定具有更有效药理活性的化合物，我们专注于蛋白水解靶向嵌合体（PROTACs），降解靶蛋白，从而抑制它们的全部功能。我们基于先前鉴定的KDM5抑制剂设计并合成了新型KDM5PROTAC候选物。细胞分析的结果表明，两种化合物，20b和23b，在神经母细胞瘤神经2a细胞中通过降解KDM5A表现出显着的神经突生长促进活性。这些结果表明,KDM5PROTACs是用于治疗神经障碍的有希望的候选药物。
