Design, Synthesis, and Structure-Activity Relationship Study of Potent MAPK11 Inhibitors

被引：2
|
作者：
Gong, Mengdie [1 ]
Tu, Mingyan [1 ]
Sun, Hongxia [1 ]
Li, Lu [1 ]
Zhu, Lili [1 ]
Li, Honglin [1 ,2 ]
Zhao, Zhenjiang [1 ]
Li, Shiliang [1 ]
机构：
[1] East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China
[2] Jiangzhong Pharmaceut Co Ltd, Nanchang 330096, Jiangxi, Peoples R China
来源：
MOLECULES | 2022年 / 27卷 / 01期
基金：
中国国家自然科学基金;
关键词：
MAPK11; Huntington's disease; mHTT protein; inhibitors; ACTIVATED PROTEIN-KINASE; HUNTINGTONS-DISEASE;
D O I：
10.3390/molecules27010203
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Huntington's disease (HD) is a rare single-gene neurodegenerative disease, which can only be treated symptomatically. Currently, there are no approved drugs for HD on the market. Studies have found that MAPK11 can serve as a potential therapeutic target for HD. Regrettably, no MAPK11 small molecule inhibitors have been approved at present. This paper presents three series of compounds that were designed and synthesized based on the structure of skepinone-L, a known MAPK14 inhibitor. Among the synthesized compounds, 13a and 13b, with IC50 values of 6.40 nM and 4.20 nM, respectively, displayed the best inhibitory activities against MAPK11. Furthermore, the structure-activity relationship (SAR) is discussed in detail, which is constructive in optimizing the MAPK11 inhibitors for better activity and effect against HD.
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页数：10
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