Discovery and optimization of 2-aminopyridine derivatives as novel and selective JAK2 inhibitors

Xiangyu Ma; Yanyan Diao; Huan Ge; Fangling Xu; Lili Zhu; Zhenjiang Zhao; Honglin Li

doi:10.1016/j.bmcl.2020.127048

Discovery and optimization of 2-aminopyridine derivatives as novel and selective JAK2 inhibitors

Xiangyu Ma
, Yanyan Diao
, Huan Ge
, Fangling Xu
, Lili Zhu^*
, Zhenjiang Zhao
, Honglin Li

^*Corresponding author for this work

East China University of Science and Technology

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

10 Scopus citations

Abstract

Janus kinases (JAKs) including JAK1, JAK2, JAK3, and TYK2 are members of a family of intracellular nonreceptor tyrosine kinases, which have been demonstrated to be critical in the cell signaling pathway and involved in inflammatory diseases and cancer. V617F mutation in JAK2 has been implicated in polycythaemia vera (PV), essential thrombocythaemia (ET) and myelofibrosis (MF). Here, we described the design, synthesis, and biological evaluation of a series of 2-aminopyridine derivatives. The results of enzymatic activity assays supported compound 16m-(R) as a potential and selective JAK2 inhibitor, which exhibited high inhibitory activity with an IC₅₀ of 3 nM against JAK2, and 85- and 76-fold selectivity over JAK1 and JAK3, respectively. Structure-activity relationships (SAR) and mechanistic analysis demonstrated that 16m-(R) might be a promising selective JAK2 inhibitor for further study.

Original language	English
Article number	127048
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	30
Issue number	8
DOIs	https://doi.org/10.1016/j.bmcl.2020.127048
State	Published - 15 Apr 2020
Externally published	Yes

Keywords

JAK2
SAR
SBDD
Selectivity

UN SDGs

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

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10.1016/j.bmcl.2020.127048

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@article{ecd90c13b2cd4b64aa54178f0fb31e76,

title = "Discovery and optimization of 2-aminopyridine derivatives as novel and selective JAK2 inhibitors",

abstract = "Janus kinases (JAKs) including JAK1, JAK2, JAK3, and TYK2 are members of a family of intracellular nonreceptor tyrosine kinases, which have been demonstrated to be critical in the cell signaling pathway and involved in inflammatory diseases and cancer. V617F mutation in JAK2 has been implicated in polycythaemia vera (PV), essential thrombocythaemia (ET) and myelofibrosis (MF). Here, we described the design, synthesis, and biological evaluation of a series of 2-aminopyridine derivatives. The results of enzymatic activity assays supported compound 16m-(R) as a potential and selective JAK2 inhibitor, which exhibited high inhibitory activity with an IC50 of 3 nM against JAK2, and 85- and 76-fold selectivity over JAK1 and JAK3, respectively. Structure-activity relationships (SAR) and mechanistic analysis demonstrated that 16m-(R) might be a promising selective JAK2 inhibitor for further study.",

keywords = "JAK2, SAR, SBDD, Selectivity",

author = "Xiangyu Ma and Yanyan Diao and Huan Ge and Fangling Xu and Lili Zhu and Zhenjiang Zhao and Honglin Li",

note = "Publisher Copyright: {\textcopyright} 2020",

year = "2020",

month = apr,

day = "15",

doi = "10.1016/j.bmcl.2020.127048",

language = "英语",

volume = "30",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Ltd",

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}

TY - JOUR

T1 - Discovery and optimization of 2-aminopyridine derivatives as novel and selective JAK2 inhibitors

AU - Ma, Xiangyu

AU - Diao, Yanyan

AU - Ge, Huan

AU - Xu, Fangling

AU - Zhu, Lili

AU - Zhao, Zhenjiang

AU - Li, Honglin

PY - 2020/4/15

Y1 - 2020/4/15

N2 - Janus kinases (JAKs) including JAK1, JAK2, JAK3, and TYK2 are members of a family of intracellular nonreceptor tyrosine kinases, which have been demonstrated to be critical in the cell signaling pathway and involved in inflammatory diseases and cancer. V617F mutation in JAK2 has been implicated in polycythaemia vera (PV), essential thrombocythaemia (ET) and myelofibrosis (MF). Here, we described the design, synthesis, and biological evaluation of a series of 2-aminopyridine derivatives. The results of enzymatic activity assays supported compound 16m-(R) as a potential and selective JAK2 inhibitor, which exhibited high inhibitory activity with an IC50 of 3 nM against JAK2, and 85- and 76-fold selectivity over JAK1 and JAK3, respectively. Structure-activity relationships (SAR) and mechanistic analysis demonstrated that 16m-(R) might be a promising selective JAK2 inhibitor for further study.

AB - Janus kinases (JAKs) including JAK1, JAK2, JAK3, and TYK2 are members of a family of intracellular nonreceptor tyrosine kinases, which have been demonstrated to be critical in the cell signaling pathway and involved in inflammatory diseases and cancer. V617F mutation in JAK2 has been implicated in polycythaemia vera (PV), essential thrombocythaemia (ET) and myelofibrosis (MF). Here, we described the design, synthesis, and biological evaluation of a series of 2-aminopyridine derivatives. The results of enzymatic activity assays supported compound 16m-(R) as a potential and selective JAK2 inhibitor, which exhibited high inhibitory activity with an IC50 of 3 nM against JAK2, and 85- and 76-fold selectivity over JAK1 and JAK3, respectively. Structure-activity relationships (SAR) and mechanistic analysis demonstrated that 16m-(R) might be a promising selective JAK2 inhibitor for further study.

KW - JAK2

KW - SAR

KW - SBDD

KW - Selectivity

UR - https://www.scopus.com/pages/publications/85080112657

U2 - 10.1016/j.bmcl.2020.127048

DO - 10.1016/j.bmcl.2020.127048

M3 - 文章

C2 - 32122740

AN - SCOPUS:85080112657

SN - 0960-894X

VL - 30

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 8

M1 - 127048

ER -

Discovery and optimization of 2-aminopyridine derivatives as novel and selective JAK2 inhibitors

Abstract

Keywords

UN SDGs

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