Design, synthesis and biological evaluation of 2-aminopyridine derivatives as USP7 inhibitors

Xiaoming Xu; Mingchen Wang; Hailong Xu; Na Liu; Kaixian Chen; Cheng Luo; Shijie Chen; Hua Chen

doi:10.1016/j.bioorg.2022.106128

Design, synthesis and biological evaluation of 2-aminopyridine derivatives as USP7 inhibitors

Xiaoming Xu, Mingchen Wang, Hailong Xu, Na Liu, Kaixian Chen, Cheng Luo, Shijie Chen^*, Hua Chen

^*Corresponding author for this work

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

8 Scopus citations

Abstract

A series of novel 2-aminopyridine derivatives 1–26 have been designed and synthesized by structural modifications on a lead USP7 inhibitor, GNE6640. All the compounds were evaluated for their USP7 inhibitory activities. The results showed that most of the compounds have good USP7 inhibitory activities at the concentration of 50 μM. Among them, compounds 7, 14 and 21 are the most potential ones from each category with the IC₅₀ values of 7.6 ± 0.1 μM, 17.0 ± 0.2 μM and 11.6 ± 0.5 μM, respectively. Compounds 7 and 21 expressed significant binding interactions with USP7 by surface plasmon resonance (SPR)-based binding assay, but both of them presented moderate antiproliferative activities against HCT116 cells. They could effectively promote MDM2 degradation, p53 stabilization and p21 gene expression in the western blot analysis.

Original language	English
Article number	106128
Journal	Bioorganic Chemistry
Volume	129
DOIs	https://doi.org/10.1016/j.bioorg.2022.106128
State	Published - Dec 2022
Externally published	Yes

Keywords

Aminopyridine
Colorectal carcinoma
MDM2
P53 and p21
Suzuki coupling reaction
USP7 inhibitors

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10.1016/j.bioorg.2022.106128

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title = "Design, synthesis and biological evaluation of 2-aminopyridine derivatives as USP7 inhibitors",

abstract = "A series of novel 2-aminopyridine derivatives 1–26 have been designed and synthesized by structural modifications on a lead USP7 inhibitor, GNE6640. All the compounds were evaluated for their USP7 inhibitory activities. The results showed that most of the compounds have good USP7 inhibitory activities at the concentration of 50 μM. Among them, compounds 7, 14 and 21 are the most potential ones from each category with the IC50 values of 7.6 ± 0.1 μM, 17.0 ± 0.2 μM and 11.6 ± 0.5 μM, respectively. Compounds 7 and 21 expressed significant binding interactions with USP7 by surface plasmon resonance (SPR)-based binding assay, but both of them presented moderate antiproliferative activities against HCT116 cells. They could effectively promote MDM2 degradation, p53 stabilization and p21 gene expression in the western blot analysis.",

keywords = "Aminopyridine, Colorectal carcinoma, MDM2, P53 and p21, Suzuki coupling reaction, USP7 inhibitors",

author = "Xiaoming Xu and Mingchen Wang and Hailong Xu and Na Liu and Kaixian Chen and Cheng Luo and Shijie Chen and Hua Chen",

note = "Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",

year = "2022",

month = dec,

doi = "10.1016/j.bioorg.2022.106128",

language = "英语",

volume = "129",

journal = "Bioorganic Chemistry",

issn = "0045-2068",

publisher = "Academic Press Inc.",

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TY - JOUR

T1 - Design, synthesis and biological evaluation of 2-aminopyridine derivatives as USP7 inhibitors

AU - Xu, Xiaoming

AU - Wang, Mingchen

AU - Xu, Hailong

AU - Liu, Na

AU - Chen, Kaixian

AU - Luo, Cheng

AU - Chen, Shijie

AU - Chen, Hua

PY - 2022/12

Y1 - 2022/12

N2 - A series of novel 2-aminopyridine derivatives 1–26 have been designed and synthesized by structural modifications on a lead USP7 inhibitor, GNE6640. All the compounds were evaluated for their USP7 inhibitory activities. The results showed that most of the compounds have good USP7 inhibitory activities at the concentration of 50 μM. Among them, compounds 7, 14 and 21 are the most potential ones from each category with the IC50 values of 7.6 ± 0.1 μM, 17.0 ± 0.2 μM and 11.6 ± 0.5 μM, respectively. Compounds 7 and 21 expressed significant binding interactions with USP7 by surface plasmon resonance (SPR)-based binding assay, but both of them presented moderate antiproliferative activities against HCT116 cells. They could effectively promote MDM2 degradation, p53 stabilization and p21 gene expression in the western blot analysis.

AB - A series of novel 2-aminopyridine derivatives 1–26 have been designed and synthesized by structural modifications on a lead USP7 inhibitor, GNE6640. All the compounds were evaluated for their USP7 inhibitory activities. The results showed that most of the compounds have good USP7 inhibitory activities at the concentration of 50 μM. Among them, compounds 7, 14 and 21 are the most potential ones from each category with the IC50 values of 7.6 ± 0.1 μM, 17.0 ± 0.2 μM and 11.6 ± 0.5 μM, respectively. Compounds 7 and 21 expressed significant binding interactions with USP7 by surface plasmon resonance (SPR)-based binding assay, but both of them presented moderate antiproliferative activities against HCT116 cells. They could effectively promote MDM2 degradation, p53 stabilization and p21 gene expression in the western blot analysis.

KW - Aminopyridine

KW - Colorectal carcinoma

KW - MDM2

KW - P53 and p21

KW - Suzuki coupling reaction

KW - USP7 inhibitors

UR - https://www.scopus.com/pages/publications/85138808641

U2 - 10.1016/j.bioorg.2022.106128

DO - 10.1016/j.bioorg.2022.106128

M3 - 文章

C2 - 36113266

AN - SCOPUS:85138808641

SN - 0045-2068

VL - 129

JO - Bioorganic Chemistry

JF - Bioorganic Chemistry

M1 - 106128

ER -

Design, synthesis and biological evaluation of 2-aminopyridine derivatives as USP7 inhibitors

Abstract

Keywords

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