Imidazo[1,2-b]pyridazines as inhibitors of DYRK kinases

Scott H. Henderson; Fiona J. Sorrell; James M. Bennett; Oleg Fedorov; Marcus T. Hanley; Paulo H. Godoi; Roberta Ruela de Sousa; Sean Robinson; Iva Hopkins Navratilova; Jonathan M. Elkins; Simon E. Ward

doi:10.1016/j.ejmech.2024.116292

Imidazo[1,2-b]pyridazines as inhibitors of DYRK kinases

Scott H. Henderson, Fiona J. Sorrell, James M. Bennett, Oleg Fedorov, Marcus T. Hanley, Paulo H. Godoi, Roberta Ruela de Sousa, Sean Robinson, Iva Hopkins Navratilova, Jonathan M. Elkins (Lead / Corresponding author), Simon E. Ward (Lead / Corresponding author)

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Abstract

Selective inhibitors of DYRK1A are of interest for the treatment of cancer, Type 2 diabetes and neurological disorders. Optimization of imidazo [1,2-b]pyridazine fragment 1 through structure−activity relationship exploration and in silico drug design efforts led to the discovery of compound 17 as a potent cellular inhibitor of DYRK1A with selectivity over much of the kinome. The binding mode of compound 17 was elucidated with X-ray crystallography, facilitating the rational design of compound 29, an imidazo [1,2-b]pyridazine with improved kinase selectivity with respect to closely related CLK kinases.

Original language	English
Article number	116292
Number of pages	14
Journal	European Journal of Medicinal Chemistry
Volume	269
Early online date	7 Mar 2024
DOIs	https://doi.org/10.1016/j.ejmech.2024.116292
Publication status	Published - 5 Apr 2024

Keywords

DYRK1A
Imidazo[1,2-b]pyridazines
Selectivity

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

UN SDGs

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

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10.1016/j.ejmech.2024.116292Licence: CC BY

Final published versionFinal published version, 4.21 MBLicence: CC BY

Cite this

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title = "Imidazo[1,2-b]pyridazines as inhibitors of DYRK kinases",

abstract = "Selective inhibitors of DYRK1A are of interest for the treatment of cancer, Type 2 diabetes and neurological disorders. Optimization of imidazo [1,2-b]pyridazine fragment 1 through structure−activity relationship exploration and in silico drug design efforts led to the discovery of compound 17 as a potent cellular inhibitor of DYRK1A with selectivity over much of the kinome. The binding mode of compound 17 was elucidated with X-ray crystallography, facilitating the rational design of compound 29, an imidazo [1,2-b]pyridazine with improved kinase selectivity with respect to closely related CLK kinases.",

keywords = "DYRK1A, Imidazo[1,2-b]pyridazines, Selectivity",

author = "Henderson, {Scott H.} and Sorrell, {Fiona J.} and Bennett, {James M.} and Oleg Fedorov and Hanley, {Marcus T.} and Godoi, {Paulo H.} and {Ruela de Sousa}, Roberta and Sean Robinson and Navratilova, {Iva Hopkins} and Elkins, {Jonathan M.} and Ward, {Simon E.}",

note = "Publisher Copyright: {\textcopyright} 2024",

year = "2024",

month = apr,

day = "5",

doi = "10.1016/j.ejmech.2024.116292",

language = "English",

volume = "269",

journal = "European Journal of Medicinal Chemistry",

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T1 - Imidazo[1,2-b]pyridazines as inhibitors of DYRK kinases

AU - Henderson, Scott H.

AU - Sorrell, Fiona J.

AU - Bennett, James M.

AU - Fedorov, Oleg

AU - Hanley, Marcus T.

AU - Godoi, Paulo H.

AU - Ruela de Sousa, Roberta

AU - Robinson, Sean

AU - Navratilova, Iva Hopkins

AU - Elkins, Jonathan M.

AU - Ward, Simon E.

PY - 2024/4/5

Y1 - 2024/4/5

N2 - Selective inhibitors of DYRK1A are of interest for the treatment of cancer, Type 2 diabetes and neurological disorders. Optimization of imidazo [1,2-b]pyridazine fragment 1 through structure−activity relationship exploration and in silico drug design efforts led to the discovery of compound 17 as a potent cellular inhibitor of DYRK1A with selectivity over much of the kinome. The binding mode of compound 17 was elucidated with X-ray crystallography, facilitating the rational design of compound 29, an imidazo [1,2-b]pyridazine with improved kinase selectivity with respect to closely related CLK kinases.

AB - Selective inhibitors of DYRK1A are of interest for the treatment of cancer, Type 2 diabetes and neurological disorders. Optimization of imidazo [1,2-b]pyridazine fragment 1 through structure−activity relationship exploration and in silico drug design efforts led to the discovery of compound 17 as a potent cellular inhibitor of DYRK1A with selectivity over much of the kinome. The binding mode of compound 17 was elucidated with X-ray crystallography, facilitating the rational design of compound 29, an imidazo [1,2-b]pyridazine with improved kinase selectivity with respect to closely related CLK kinases.

KW - DYRK1A

KW - Imidazo[1,2-b]pyridazines

KW - Selectivity

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SN - 0223-5234

VL - 269

JO - European Journal of Medicinal Chemistry

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ER -

Imidazo[1,2-b]pyridazines as inhibitors of DYRK kinases

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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EUbOPEN: Enabling and Unlocking biology in the OPEN (Joint with Goethe University Frankfurt, University of Oxford, Karolinska Institute and 9 others)

Cite this

Imidazo[1,2-b]pyridazines as inhibitors of DYRK kinases

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

EUbOPEN: Enabling and Unlocking biology in the OPEN (Joint with Goethe University Frankfurt, University of Oxford, Karolinska Institute and 9 others)

Cite this