4-([1,2,4]Triazolo[1,5-a]pyridin-6-yl)-5(3)-(6-methylpyridin-2-yl)imidazole and -pyrazole derivatives as potent and selective inhibitors of transforming growth factor-β type i receptor kinase

Cheng Hua Jin; Maddeboina Krishnaiah; Domalapally Sreenu; Vura Bala Subrahmanyam; Hyun Ju Park; So Jung Park; Yhun Yhong Sheen; Dae Kee Kim

doi:10.1016/j.bmc.2014.03.022

4-([1,2,4]Triazolo[1,5-a]pyridin-6-yl)-5(3)-(6-methylpyridin-2-yl)imidazole and -pyrazole derivatives as potent and selective inhibitors of transforming growth factor-β type i receptor kinase

Cheng Hua Jin, Maddeboina Krishnaiah, Domalapally Sreenu, Vura Bala Subrahmanyam, Hyun Ju Park, So Jung Park, Yhun Yhong Sheen, Dae Kee Kim

Department of Pharmaceutical Sciences

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

35 Scopus citations

Abstract

A series of 4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5(3)-(6-methylpyridin-2- yl)imidazoles and -pyrazoles 14a-c, 15a-c, 16a, 16b, 19a-d, 21a, and 21b has been synthesized and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. Among them, the pyrazole derivative 21b inhibited ALK5 phosphorylation with an IC₅₀ value of 0.018 μM and showed 95% inhibition at 0.03 μM in a luciferase reporter assay using HaCaT cells permanently transfected with p3TP-luc reporter construct. The 21b showed a high selectivity index of 284 against p38α MAP kinase. The binding pose of 21b generated by docking analysis reveals that it fits well into the ATP binding cavity of ALK5 by forming several hydrogen bond interactions.

Original language	English
Pages (from-to)	2724-2732
Number of pages	9
Journal	Bioorganic and Medicinal Chemistry
Volume	22
Issue number	9
DOIs	https://doi.org/10.1016/j.bmc.2014.03.022
State	Published - 1 May 2014

Bibliographical note

Funding Information:
This work was supported by RP-Grant 2011 of Ewha Womans University.

Keywords

ALK5 inhibitor
Cancer
Cell-based luciferase reporter assay
Docking
Fibrosis
Kinase assay
TGF-β

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10.1016/j.bmc.2014.03.022

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Jin, C. H., Krishnaiah, M., Sreenu, D., Subrahmanyam, V. B., Park, H. J., Park, S. J., Sheen, Y. Y., & Kim, D. K. (2014). 4-([1,2,4]Triazolo[1,5-a]pyridin-6-yl)-5(3)-(6-methylpyridin-2-yl)imidazole and -pyrazole derivatives as potent and selective inhibitors of transforming growth factor-β type i receptor kinase. Bioorganic and Medicinal Chemistry, 22(9), 2724-2732. https://doi.org/10.1016/j.bmc.2014.03.022

@article{cacbeff5c2ad423396a675fe1085b57b,

title = "4-([1,2,4]Triazolo[1,5-a]pyridin-6-yl)-5(3)-(6-methylpyridin-2-yl)imidazole and -pyrazole derivatives as potent and selective inhibitors of transforming growth factor-β type i receptor kinase",

abstract = "A series of 4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5(3)-(6-methylpyridin-2- yl)imidazoles and -pyrazoles 14a-c, 15a-c, 16a, 16b, 19a-d, 21a, and 21b has been synthesized and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. Among them, the pyrazole derivative 21b inhibited ALK5 phosphorylation with an IC50 value of 0.018 μM and showed 95% inhibition at 0.03 μM in a luciferase reporter assay using HaCaT cells permanently transfected with p3TP-luc reporter construct. The 21b showed a high selectivity index of 284 against p38α MAP kinase. The binding pose of 21b generated by docking analysis reveals that it fits well into the ATP binding cavity of ALK5 by forming several hydrogen bond interactions.",

keywords = "ALK5 inhibitor, Cancer, Cell-based luciferase reporter assay, Docking, Fibrosis, Kinase assay, TGF-β",

author = "Jin, {Cheng Hua} and Maddeboina Krishnaiah and Domalapally Sreenu and Subrahmanyam, {Vura Bala} and Park, {Hyun Ju} and Park, {So Jung} and Sheen, {Yhun Yhong} and Kim, {Dae Kee}",

note = "Funding Information: This work was supported by RP-Grant 2011 of Ewha Womans University. ",

year = "2014",

month = may,

day = "1",

doi = "10.1016/j.bmc.2014.03.022",

language = "English",

volume = "22",

pages = "2724--2732",

journal = "Bioorganic and Medicinal Chemistry",

issn = "0968-0896",

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Jin, CH, Krishnaiah, M, Sreenu, D, Subrahmanyam, VB, Park, HJ, Park, SJ, Sheen, YY & Kim, DK 2014, '4-([1,2,4]Triazolo[1,5-a]pyridin-6-yl)-5(3)-(6-methylpyridin-2-yl)imidazole and -pyrazole derivatives as potent and selective inhibitors of transforming growth factor-β type i receptor kinase', Bioorganic and Medicinal Chemistry, vol. 22, no. 9, pp. 2724-2732. https://doi.org/10.1016/j.bmc.2014.03.022

4-([1,2,4]Triazolo[1,5-a]pyridin-6-yl)-5(3)-(6-methylpyridin-2-yl)imidazole and -pyrazole derivatives as potent and selective inhibitors of transforming growth factor-β type i receptor kinase. / Jin, Cheng Hua; Krishnaiah, Maddeboina; Sreenu, Domalapally et al.
In: Bioorganic and Medicinal Chemistry, Vol. 22, No. 9, 01.05.2014, p. 2724-2732.

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

TY - JOUR

T1 - 4-([1,2,4]Triazolo[1,5-a]pyridin-6-yl)-5(3)-(6-methylpyridin-2-yl)imidazole and -pyrazole derivatives as potent and selective inhibitors of transforming growth factor-β type i receptor kinase

AU - Jin, Cheng Hua

AU - Krishnaiah, Maddeboina

AU - Sreenu, Domalapally

AU - Subrahmanyam, Vura Bala

AU - Park, Hyun Ju

AU - Park, So Jung

AU - Sheen, Yhun Yhong

AU - Kim, Dae Kee

N1 - Funding Information: This work was supported by RP-Grant 2011 of Ewha Womans University.

PY - 2014/5/1

Y1 - 2014/5/1

N2 - A series of 4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5(3)-(6-methylpyridin-2- yl)imidazoles and -pyrazoles 14a-c, 15a-c, 16a, 16b, 19a-d, 21a, and 21b has been synthesized and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. Among them, the pyrazole derivative 21b inhibited ALK5 phosphorylation with an IC50 value of 0.018 μM and showed 95% inhibition at 0.03 μM in a luciferase reporter assay using HaCaT cells permanently transfected with p3TP-luc reporter construct. The 21b showed a high selectivity index of 284 against p38α MAP kinase. The binding pose of 21b generated by docking analysis reveals that it fits well into the ATP binding cavity of ALK5 by forming several hydrogen bond interactions.

AB - A series of 4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5(3)-(6-methylpyridin-2- yl)imidazoles and -pyrazoles 14a-c, 15a-c, 16a, 16b, 19a-d, 21a, and 21b has been synthesized and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. Among them, the pyrazole derivative 21b inhibited ALK5 phosphorylation with an IC50 value of 0.018 μM and showed 95% inhibition at 0.03 μM in a luciferase reporter assay using HaCaT cells permanently transfected with p3TP-luc reporter construct. The 21b showed a high selectivity index of 284 against p38α MAP kinase. The binding pose of 21b generated by docking analysis reveals that it fits well into the ATP binding cavity of ALK5 by forming several hydrogen bond interactions.

KW - ALK5 inhibitor

KW - Cancer

KW - Cell-based luciferase reporter assay

KW - Docking

KW - Fibrosis

KW - Kinase assay

KW - TGF-β

UR - http://www.scopus.com/inward/record.url?scp=84899455861&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2014.03.022

DO - 10.1016/j.bmc.2014.03.022

M3 - Article

C2 - 24704197

AN - SCOPUS:84899455861

SN - 0968-0896

VL - 22

SP - 2724

EP - 2732

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 9

ER -

4-([1,2,4]Triazolo[1,5-a]pyridin-6-yl)-5(3)-(6-methylpyridin-2-yl)imidazole and -pyrazole derivatives as potent and selective inhibitors of transforming growth factor-β type i receptor kinase

Abstract

Bibliographical note

Keywords

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