Discovery and Characterization of Selective and Ligand-Efficient DYRK Inhibitors

Scott H. Henderson; Fiona Sorrell; James Bennett; Oleg Fedorov; Marcus T. Hanley; Paulo H. Godoi; Roberta Ruela de Sousa; Sean Robinson; Alexander Ashall-Kelly; Iva Hopkins Navratilova; Daryl S. Walter; Jonathan M. Elkins; Simon E. Ward

doi:10.1021/acs.jmedchem.1c01115

Discovery and Characterization of Selective and Ligand-Efficient DYRK Inhibitors

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

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

18 Citations (Scopus)

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Abstract

Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) regulates the proliferation and differentiation of neuronal progenitor cells during brain development. Consequently, DYRK1A has attracted interest as a target for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD) and Down's syndrome. Recently, the inhibition of DYRK1A has been investigated as a potential treatment for diabetes, while DYRK1A's role as a mediator in the cell cycle has garnered interest in oncologic indications. Structure-activity relationship (SAR) analysis in combination with high-resolution X-ray crystallography leads to a series of pyrazolo[1,5-b]pyridazine inhibitors with excellent ligand efficiencies, good physicochemical properties, and a high degree of selectivity over the kinome. Compound 11 exhibited good permeability and cellular activity without P-glycoprotein liability, extending the utility of 11 in an in vivo setting. These pyrazolo[1,5-b]pyridazines are a viable lead series in the discovery of new therapies for the treatment of diseases linked to DYRK1A function.

Original language	English
Pages (from-to)	11709-11728
Number of pages	20
Journal	Journal of Medicinal Chemistry
Volume	64
Issue number	15
Early online date	3 Aug 2021
DOIs	https://doi.org/10.1021/acs.jmedchem.1c01115
Publication status	Published - 12 Aug 2021

UN SDGs

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

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

Drug Discovery
Molecular Medicine

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Final published versionFinal published version, 3.66 MBLicence: CC BY-NC-ND

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Henderson, S. H., Sorrell, F., Bennett, J., Fedorov, O., Hanley, M. T., Godoi, P. H., Ruela de Sousa, R., Robinson, S., Ashall-Kelly, A., Hopkins Navratilova, I., Walter, D. S., Elkins, J. M., & Ward, S. E. (2021). Discovery and Characterization of Selective and Ligand-Efficient DYRK Inhibitors. Journal of Medicinal Chemistry, 64(15), 11709-11728. https://doi.org/10.1021/acs.jmedchem.1c01115

@article{d7acc2eee2b7462eabb469fd89e8d124,

title = "Discovery and Characterization of Selective and Ligand-Efficient DYRK Inhibitors",

abstract = "Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) regulates the proliferation and differentiation of neuronal progenitor cells during brain development. Consequently, DYRK1A has attracted interest as a target for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD) and Down's syndrome. Recently, the inhibition of DYRK1A has been investigated as a potential treatment for diabetes, while DYRK1A's role as a mediator in the cell cycle has garnered interest in oncologic indications. Structure-activity relationship (SAR) analysis in combination with high-resolution X-ray crystallography leads to a series of pyrazolo[1,5-b]pyridazine inhibitors with excellent ligand efficiencies, good physicochemical properties, and a high degree of selectivity over the kinome. Compound 11 exhibited good permeability and cellular activity without P-glycoprotein liability, extending the utility of 11 in an in vivo setting. These pyrazolo[1,5-b]pyridazines are a viable lead series in the discovery of new therapies for the treatment of diseases linked to DYRK1A function.",

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

note = "Funding - S.H.H. is funded by the BBSRC (BB/L017105/1). S.E.W. is funded by the Wellcome Trust, MRC, BBSRC and the European Structural Funding via Ser Cymru scheme. R.R.d.S.{\^ } is funded by Sao Paulo Research Foundation-FAPESP 2016/{\~ }17469-0 and 13/50724-5. The SGC is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada, Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD grant no. 115766], Janssen, Merck KGaA Darmstadt Germany, MSD, Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, Sao Paulo Research Foundation-FAPESP, Takeda, and Wellcome [106169/ZZ14/Z].",

year = "2021",

month = aug,

day = "12",

doi = "10.1021/acs.jmedchem.1c01115",

language = "English",

volume = "64",

pages = "11709--11728",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "15",

}

Henderson, SH, Sorrell, F, Bennett, J, Fedorov, O, Hanley, MT, Godoi, PH, Ruela de Sousa, R, Robinson, S, Ashall-Kelly, A, Hopkins Navratilova, I, Walter, DS, Elkins, JM & Ward, SE 2021, 'Discovery and Characterization of Selective and Ligand-Efficient DYRK Inhibitors', Journal of Medicinal Chemistry, vol. 64, no. 15, pp. 11709-11728. https://doi.org/10.1021/acs.jmedchem.1c01115

TY - JOUR

T1 - Discovery and Characterization of Selective and Ligand-Efficient DYRK Inhibitors

AU - Henderson, Scott H.

AU - Sorrell, Fiona

AU - Bennett, James

AU - Fedorov, Oleg

AU - Hanley, Marcus T.

AU - Godoi, Paulo H.

AU - Ruela de Sousa, Roberta

AU - Robinson, Sean

AU - Ashall-Kelly, Alexander

AU - Hopkins Navratilova, Iva

AU - Walter, Daryl S.

AU - Elkins, Jonathan M.

AU - Ward, Simon E.

N1 - Funding - S.H.H. is funded by the BBSRC (BB/L017105/1). S.E.W. is funded by the Wellcome Trust, MRC, BBSRC and the European Structural Funding via Ser Cymru scheme. R.R.d.S. ̂ is funded by Sao Paulo Research Foundation-FAPESP 2016/ ̃17469-0 and 13/50724-5. The SGC is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada, Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD grant no. 115766], Janssen, Merck KGaA Darmstadt Germany, MSD, Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, Sao Paulo Research Foundation-FAPESP, Takeda, and Wellcome [106169/ZZ14/Z].

PY - 2021/8/12

Y1 - 2021/8/12

N2 - Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) regulates the proliferation and differentiation of neuronal progenitor cells during brain development. Consequently, DYRK1A has attracted interest as a target for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD) and Down's syndrome. Recently, the inhibition of DYRK1A has been investigated as a potential treatment for diabetes, while DYRK1A's role as a mediator in the cell cycle has garnered interest in oncologic indications. Structure-activity relationship (SAR) analysis in combination with high-resolution X-ray crystallography leads to a series of pyrazolo[1,5-b]pyridazine inhibitors with excellent ligand efficiencies, good physicochemical properties, and a high degree of selectivity over the kinome. Compound 11 exhibited good permeability and cellular activity without P-glycoprotein liability, extending the utility of 11 in an in vivo setting. These pyrazolo[1,5-b]pyridazines are a viable lead series in the discovery of new therapies for the treatment of diseases linked to DYRK1A function.

AB - Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) regulates the proliferation and differentiation of neuronal progenitor cells during brain development. Consequently, DYRK1A has attracted interest as a target for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD) and Down's syndrome. Recently, the inhibition of DYRK1A has been investigated as a potential treatment for diabetes, while DYRK1A's role as a mediator in the cell cycle has garnered interest in oncologic indications. Structure-activity relationship (SAR) analysis in combination with high-resolution X-ray crystallography leads to a series of pyrazolo[1,5-b]pyridazine inhibitors with excellent ligand efficiencies, good physicochemical properties, and a high degree of selectivity over the kinome. Compound 11 exhibited good permeability and cellular activity without P-glycoprotein liability, extending the utility of 11 in an in vivo setting. These pyrazolo[1,5-b]pyridazines are a viable lead series in the discovery of new therapies for the treatment of diseases linked to DYRK1A function.

UR - https://www.scopus.com/pages/publications/85113707719

U2 - 10.1021/acs.jmedchem.1c01115

DO - 10.1021/acs.jmedchem.1c01115

M3 - Article

C2 - 34342227

SN - 0022-2623

VL - 64

SP - 11709

EP - 11728

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 15

ER -

Discovery and Characterization of Selective and Ligand-Efficient DYRK Inhibitors

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