Discovery and Characterization of Selective and Ligand-Efficient DYRK Inhibitors

Author(s):Show less -

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]

Affiliation

^[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

• Document type: Journal article
• Source: Journal of Medicinal Chemistry; v. 64, n. 15, p. 11709-11728, AUG 12 2021.
• Web of Science Citations: 0

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. (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