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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Discovery and Characterization of Selective and Ligand-Efficient DYRK Inhibitors

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Henderson, Scott H. [1, 2] ; Sorrell, Fiona [3] ; Bennett, James [4] ; Fedorov, Oleg [4] ; Hanley, Marcus T. [5] ; Godoi, Paulo H. [6] ; de Sousa, Roberta Ruela [6] ; Robinson, Sean [7] ; Ashall-Kelly, Alexander [5] ; Navratilova, Iva Hopkins [7, 8] ; Walter, Daryl S. [9] ; Elkins, Jonathan M. [3, 6] ; Ward, Simon E. [5]
Total Authors: 13
[1] Univ Sussex, Sussex Drug Discovery Ctr, Brighton BN1 9RH, E Sussex - England
[2] BenevolentAI, Minerva Bldg, Babraham Hall, Cambridge CB22 3AT - England
[3] Univ Oxford, Struct Genom Consortium, Oxford OX3 7DQ - England
[4] Univ Oxford, Target Discovery Inst, Oxford OX3 7FZ - England
[5] Cardiff Univ, Med Discovery Inst, Cardiff CF10 3AT - Wales
[6] Univ Estadual Campinas, Struct Genom Consortium, BR-13083886 Campinas, SP - Brazil
[7] Exscientia, Oxford OX4 4GE - England
[8] Univ Dundee, Dundee DD1 5EH - Scotland
[9] Evotec UK Ltd, Abingdon OX14 4RZ, Oxon - England
Total Affiliations: 9
Document type: Journal article
Source: Journal of Medicinal Chemistry; v. 64, n. 15, p. 11709-11728, AUG 12 2021.
Web of Science Citations: 0

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. (AU)

FAPESP's process: 16/17469-0 - Development of celular assays to measure and to discover the phenotypic consequences of chemical inhibition of Vaccinia-Related Kinase 1 (VRK1)
Grantee:Roberta Regina Ruela de Sousa
Support Opportunities: Scholarships in Brazil - Post-Doctoral
FAPESP's process: 13/50724-5 - Protein Kinase Chemical Biology Center: supporting drug development through open-access research
Grantee:Paulo Arruda
Support Opportunities: Research Grants - Research Partnership for Technological Innovation - PITE