Graduate School of Medical Science, Kyoto Prefectural University of Medicine.
SANKEN, Osaka University.
Chem Pharm Bull (Tokyo). 2024;72(7):638-647. doi: 10.1248/cpb.c23-00026.
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.
赖氨酸去甲基化酶 5（KDM5）蛋白参与多种神经疾病，包括阿尔茨海默病，抑制 KDM5 有望成为这些疾病的治疗策略。然而，传统 KDM5 抑制剂的药理作用不足，因为它们仅针对 KDM5 的催化功能。为了鉴定具有更强药理活性的化合物，我们专注于蛋白水解靶向嵌合体（PROTAC），它可以降解靶蛋白，从而抑制其全部功能。我们基于先前鉴定的 KDM5 抑制剂设计并合成了新型 KDM5 PROTAC 候选物。细胞测定的结果表明，两种化合物 20b 和 23b 通过在神经母细胞瘤Neuro 2a 细胞中降解 KDM5A 表现出显著的促进神经突生长活性。这些结果表明 KDM5 PROTAC 是治疗神经疾病的有前途的药物候选物。
