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Design, synthesis, and structure–activity relationship of TAK-418 and its derivatives as a novel series of LSD1 inhibitors with lowered risk of hematological side effects
European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2022-06-07 , DOI: 10.1016/j.ejmech.2022.114522
Yasushi Hattori 1 , Shigemitsu Matsumoto 1 , Shinji Morimoto 1 , Masaki Daini 1 , Masashi Toyofuku 1 , Satoru Matsuda 1 , Rina Baba 1 , Koji Murakami 1 , Misa Iwatani 1 , Hideyuki Oki 1 , Shinji Iwasaki 1 , Kouta Matsumiya 1 , Yusuke Tominari 1 , Haruhide Kimura 1 , Mitsuhiro Ito 1
Affiliation  

Lysine-specific demethylase 1 (LSD1) is an enzyme that demethylates methylated histone H3 lysine 4 (H3K4). Inhibition of LSD1 enzyme activity could increase H3K4 methylation levels and treat diseases associated with epigenetic dysregulation. However, known LSD1 inhibitors disrupt the interaction between LSD1 and cofactors such as GFI1B, causing the risk of hematological toxicity, including thrombocytopenia. Starting from a known LSD1 inhibitor (±)1 as a lead compound, a novel series of LSD1 inhibitors that do not induce the expression of GFI1 mRNA, an in vitro surrogate marker of LSD1-GFI1B dissociation, has been designed and synthesized. Initial structure–activity relationship (SAR) studies revealed the structural features key to avoiding GFI1 mRNA induction. Such SAR information enables optimization of LSD1 inhibitors with lowered risk of hematological side effects; TAK-418 ((1R,2R)-2n), the clinical candidate compound found through this optimization, has a hematological safety profile in rodents and humans. We further confirmed that oral administration of TAK-418 at 0.3 and 1 mg/kg for 2 weeks ameliorated memory deficits in mice with NMDA receptor hypofunction, suggesting potential of efficacy in neurodevelopmental disorders. TAK-418 warrants further investigation as a novel class of LSD1 inhibitors with a superior safety profile for the treatment of CNS disorders.



中文翻译:

TAK-418 及其衍生物的设计、合成和构效关系作为降低血液学副作用风险的新型 LSD1 抑制剂系列

赖氨酸特异性去甲基化酶 1 (LSD1) 是一种将甲基化组蛋白 H3 赖氨酸 4 (H3K4) 去甲基化的酶。抑制 LSD1 酶活性可以增加 H3K4 甲基化水平并治疗与表观遗传失调相关的疾病。然而,已知的 LSD1 抑制剂会破坏 LSD1 与 GFI1B 等辅助因子之间的相互作用,从而导致血液学毒性风险,包括血小板减少症。从已知的 LSD1 抑制剂 (±) 1作为先导化合物开始,已经设计和合成了一系列不诱导 GFI1 mRNA 表达的新型 LSD1 抑制剂,GFI1 mRNA是 LSD1-GFI1B 解离的体外替代标志物。初始构效关系 (SAR) 研究揭示了避免GFI1的关键结构特征mRNA诱导。此类 SAR 信息能够优化 LSD1 抑制剂,降低血液学副作用的风险;TAK-418 ((1 R, 2 R ) - 2n ) 是通过这种优化发现的临床候选化合物,在啮齿动物和人类中具有血液学安全性。我们进一步证实,口服 0.3 和 1 mg/kg 的 TAK-418 2 周可改善 NMDA 受体机能减退小鼠的记忆缺陷,表明其在神经发育障碍中的疗效潜力。TAK-418 作为一种新型 LSD1 抑制剂,在治疗中枢神经系统疾病方面具有卓越的安全性,值得进一步研究。

更新日期:2022-06-07
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