Design, synthesis and SAR study of 2-aminopyridine derivatives as potent and selective JAK2 inhibitors

Dandan Liu; Huan Ge; Fangling Xu; Yufang Xu; Wenjun Liu; Honglin Li; Lili Zhu; Yanyan Diao; Zhenjiang Zhao

doi:10.1016/j.cclet.2021.12.099

Design, synthesis and SAR study of 2-aminopyridine derivatives as potent and selective JAK2 inhibitors

Dandan Liu
, Huan Ge
, Fangling Xu
, Yufang Xu
, Wenjun Liu
, Honglin Li
, Lili Zhu^*
, Yanyan Diao
, Zhenjiang Zhao

^*Corresponding author for this work

East China University of Science and Technology
Jiangzhong Pharmaceutical Co., Ltd.

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

8 Scopus citations

Abstract

The abnormal activation of JAK2 kinase is closely related to the occurrence and progression of myeloproliferative neoplasms (MPNs). At present, there is still an obvious unmet medical need for selective JAK2 inhibitors in clinic. In this paper, a class of 2-aminopyridine derivatives as potent and selective JAK2 inhibitors was obtained by combining drug design, synthesis and structure-activity relationship studies based on the previously identified lead Crizotinib. Among them, 21b exhibited high inhibitory activity against JAK2 with an IC₅₀ of 9 nmol/L, moreover, it showed 276- and 184-fold selectivity over JAK1 and JAK3, respectively. Besides, 21b had a significant antiproliferative activity against HEL cells, and also inhibited the phosphorylation of JAK2 and its down-stream signaling pathway. These results indicated that 2-aminopyridine compound 21b had the potential to be developed as a selective JAK2 inhibitor for further study.

Original language	English
Pages (from-to)	2969-2974
Number of pages	6
Journal	Chinese Chemical Letters
Volume	33
Issue number	6
DOIs	https://doi.org/10.1016/j.cclet.2021.12.099
State	Published - Jun 2022
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Cancer
Inhibitors
JAK2
Selectivity
Structure-activity relationships

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10.1016/j.cclet.2021.12.099

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title = "Design, synthesis and SAR study of 2-aminopyridine derivatives as potent and selective JAK2 inhibitors",

abstract = "The abnormal activation of JAK2 kinase is closely related to the occurrence and progression of myeloproliferative neoplasms (MPNs). At present, there is still an obvious unmet medical need for selective JAK2 inhibitors in clinic. In this paper, a class of 2-aminopyridine derivatives as potent and selective JAK2 inhibitors was obtained by combining drug design, synthesis and structure-activity relationship studies based on the previously identified lead Crizotinib. Among them, 21b exhibited high inhibitory activity against JAK2 with an IC50 of 9 nmol/L, moreover, it showed 276- and 184-fold selectivity over JAK1 and JAK3, respectively. Besides, 21b had a significant antiproliferative activity against HEL cells, and also inhibited the phosphorylation of JAK2 and its down-stream signaling pathway. These results indicated that 2-aminopyridine compound 21b had the potential to be developed as a selective JAK2 inhibitor for further study.",

keywords = "Cancer, Inhibitors, JAK2, Selectivity, Structure-activity relationships",

author = "Dandan Liu and Huan Ge and Fangling Xu and Yufang Xu and Wenjun Liu and Honglin Li and Lili Zhu and Yanyan Diao and Zhenjiang Zhao",

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

year = "2022",

month = jun,

doi = "10.1016/j.cclet.2021.12.099",

language = "英语",

volume = "33",

pages = "2969--2974",

journal = "Chinese Chemical Letters",

issn = "1001-8417",

publisher = "Elsevier B.V.",

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}

TY - JOUR

T1 - Design, synthesis and SAR study of 2-aminopyridine derivatives as potent and selective JAK2 inhibitors

AU - Liu, Dandan

AU - Ge, Huan

AU - Xu, Fangling

AU - Xu, Yufang

AU - Liu, Wenjun

AU - Li, Honglin

AU - Zhu, Lili

AU - Diao, Yanyan

AU - Zhao, Zhenjiang

PY - 2022/6

Y1 - 2022/6

N2 - The abnormal activation of JAK2 kinase is closely related to the occurrence and progression of myeloproliferative neoplasms (MPNs). At present, there is still an obvious unmet medical need for selective JAK2 inhibitors in clinic. In this paper, a class of 2-aminopyridine derivatives as potent and selective JAK2 inhibitors was obtained by combining drug design, synthesis and structure-activity relationship studies based on the previously identified lead Crizotinib. Among them, 21b exhibited high inhibitory activity against JAK2 with an IC50 of 9 nmol/L, moreover, it showed 276- and 184-fold selectivity over JAK1 and JAK3, respectively. Besides, 21b had a significant antiproliferative activity against HEL cells, and also inhibited the phosphorylation of JAK2 and its down-stream signaling pathway. These results indicated that 2-aminopyridine compound 21b had the potential to be developed as a selective JAK2 inhibitor for further study.

AB - The abnormal activation of JAK2 kinase is closely related to the occurrence and progression of myeloproliferative neoplasms (MPNs). At present, there is still an obvious unmet medical need for selective JAK2 inhibitors in clinic. In this paper, a class of 2-aminopyridine derivatives as potent and selective JAK2 inhibitors was obtained by combining drug design, synthesis and structure-activity relationship studies based on the previously identified lead Crizotinib. Among them, 21b exhibited high inhibitory activity against JAK2 with an IC50 of 9 nmol/L, moreover, it showed 276- and 184-fold selectivity over JAK1 and JAK3, respectively. Besides, 21b had a significant antiproliferative activity against HEL cells, and also inhibited the phosphorylation of JAK2 and its down-stream signaling pathway. These results indicated that 2-aminopyridine compound 21b had the potential to be developed as a selective JAK2 inhibitor for further study.

KW - Cancer

KW - Inhibitors

KW - JAK2

KW - Selectivity

KW - Structure-activity relationships

UR - https://www.scopus.com/pages/publications/85124224053

U2 - 10.1016/j.cclet.2021.12.099

DO - 10.1016/j.cclet.2021.12.099

M3 - 文章

AN - SCOPUS:85124224053

SN - 1001-8417

VL - 33

SP - 2969

EP - 2974

JO - Chinese Chemical Letters

JF - Chinese Chemical Letters

IS - 6

ER -

Design, synthesis and SAR study of 2-aminopyridine derivatives as potent and selective JAK2 inhibitors

Abstract

UN SDGs

Keywords

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