Design, synthesis, and structure–activity relationship study of potent mapk11 inhibitors

Mengdie Gong; Mingyan Tu; Hongxia Sun; Lu Li; Lili Zhu; Honglin Li; Zhenjiang Zhao; Shiliang Li

doi:10.3390/molecules27010203

Design, synthesis, and structure–activity relationship study of potent mapk11 inhibitors

Mengdie Gong, Mingyan Tu, Hongxia Sun, Lu Li, Lili Zhu, Honglin Li, Zhenjiang Zhao, Shiliang Li

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

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.

Original language	English
Article number	203
Journal	Molecules
Volume	27
Issue number	1
DOIs	https://doi.org/10.3390/molecules27010203
State	Published - 1 Jan 2022
Externally published	Yes

Keywords

Huntington’s disease
Inhibitors
MAPK11
MHTT protein

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10.3390/molecules27010203

Cite this

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title = "Design, synthesis, and structure–activity relationship study of potent mapk11 inhibitors",

abstract = "Huntington{\textquoteright}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.",

keywords = "Huntington{\textquoteright}s disease, Inhibitors, MAPK11, MHTT protein",

author = "Mengdie Gong and Mingyan Tu and Hongxia Sun and Lu Li and Lili Zhu and Honglin Li and Zhenjiang Zhao and Shiliang Li",

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T1 - Design, synthesis, and structure–activity relationship study of potent mapk11 inhibitors

AU - Gong, Mengdie

AU - Tu, Mingyan

AU - Sun, Hongxia

AU - Li, Lu

AU - Zhu, Lili

AU - Li, Honglin

AU - Zhao, Zhenjiang

AU - Li, Shiliang

PY - 2022/1/1

Y1 - 2022/1/1

N2 - 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.

AB - 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.

KW - Huntington’s disease

KW - Inhibitors

KW - MAPK11

KW - MHTT protein

UR - https://www.scopus.com/pages/publications/85122038505

U2 - 10.3390/molecules27010203

DO - 10.3390/molecules27010203

M3 - 文章

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Design, synthesis, and structure–activity relationship study of potent mapk11 inhibitors

Abstract

Keywords

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