Discovery and characterization of selective and ligand-efficient DYRK inhibitors

Henderson, Scott H, Sorrell, Fiona, Bennett, James, Fedorov, Oleg, Hanley, Marcus T, Godoi, Paulo H, Ruela De Sousa, Roberta, Robinson, Sean, Ashall-Kelly, Alexander, Hopkins Navratilova, Iva, Walter, Daryl S, Elkins, Jonathan M and Ward, Simon E (2021) Discovery and characterization of selective and ligand-efficient DYRK inhibitors. Journal of Medicinal Chemistry, 64 (15). pp. 11709-11728. ISSN 0022-2623

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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.

Item Type: Article
Keywords: Dose-Response Relationship, Drug, Drug Discovery, HEK293 Cells, Humans, Ligands, Molecular Structure, Protein Kinase Inhibitors, Protein Serine-Threonine Kinases, Protein-Tyrosine Kinases, Solubility, Structure-Activity Relationship
Schools and Departments: School of Life Sciences > Chemistry
SWORD Depositor: Mx Elements Account
Depositing User: Mx Elements Account
Date Deposited: 19 May 2022 08:40
Last Modified: 19 May 2022 08:45
URI: http://sro.sussex.ac.uk/id/eprint/106002

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