Identification of Proteolysis Targeting Chimeras (PROTACs) for Lysine Demethylase 5 and Their Neurite Outgrowth-Promoting Activity.

IF 1.5 4区医学 Q4 CHEMISTRY, MEDICINAL

Chemical & pharmaceutical bulletin Pub Date : 2024-01-01 DOI:10.1248/cpb.c23-00026

Tetsuya Iida, Yukihiro Itoh, Yukari Takahashi, Yuka Miyake, Farzad Zamani, Yasunobu Yamashita, Yuri Takada, Toshiki Akiyama, Jun Ibaraki, Kyoka Okuda, Yuto Tokuda, Tomoka Nishimura, Koto Hidaka, Hiiro Mori, Makoto Oba, Takayoshi Suzuki

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引用次数: 0

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.

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鉴定赖氨酸去甲基化酶 5 的蛋白水解靶向嵌合体 (PROTAC) 及其促进神经元生长的活性

赖氨酸去甲基化酶 5（KDM5）蛋白与包括阿尔茨海默病在内的多种神经系统疾病有关，抑制 KDM5 有望成为治疗这些疾病的一种策略。然而，传统的 KDM5 抑制剂仅针对 KDM5 的催化功能，药理作用不足。为了找出具有更强药理活性的化合物，我们把重点放在了蛋白水解靶向嵌合体（PROTACs）上，这种嵌合体能降解靶蛋白，从而抑制其全部功能。我们以之前鉴定的 KDM5 抑制剂为基础，设计并合成了新型 KDM5 PROTAC 候选化合物。细胞实验结果显示，20b 和 23b 这两种化合物通过降解神经母细胞瘤神经 2a 细胞中的 KDM5A，表现出显著的促进神经元生长活性。这些结果表明，KDM5 PROTACs 是治疗神经系统疾病的有望候选药物。

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来源期刊

Chemical & pharmaceutical bulletin 医学-化学综合

CiteScore

3.20

自引率

5.90%

发文量

132

审稿时长

1.7 months

期刊介绍： The CPB covers various chemical topics in the pharmaceutical and health sciences fields dealing with biologically active compounds, natural products, and medicines, while BPB deals with a wide range of biological topics in the pharmaceutical and health sciences fields including scientific research from basic to clinical studies. For details of their respective scopes, please refer to the submission topic categories below. Topics: Organic chemistry In silico science Inorganic chemistry Pharmacognosy Health statistics Forensic science Biochemistry Pharmacology Pharmaceutical care and science Medicinal chemistry Analytical chemistry Physical pharmacy Natural product chemistry Toxicology Environmental science Molecular and cellular biology Biopharmacy and pharmacokinetics Pharmaceutical education Chemical biology Physical chemistry Pharmaceutical engineering Epidemiology Hygiene Regulatory science Immunology and microbiology Clinical pharmacy Miscellaneous.