Mining public domain data to develop selective DYRK1A inhibitors

DOI: 10.1021/acsmedchemlett.0c00279

Authors: Scott H. Henderson (University of Sussex) , Fiona Sorrell (Structural Genomics Consortium, University of Oxford) , James Bennett (Target Discovery Institute, University of Oxford) , Marcus T. Hanley (Medicines Discovery Institute, Cardiff University) , Sean Robinson (Exscientia) , Iva Hopkins Navratilova (Exscientia; University of Dundee) , Jonathan M. Elkins (Structural Genomics Consortium, University of Oxford; Structural Genomics Consortium, Universidade Estadual de Campinas, Cidade Universitária Zeferino Vaz) , Simon E. Ward (Medicines Discovery Institute, Cardiff University)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Acs Medicinal Chemistry Letters , VOL 11 , PAGES 1620 - 1626

State: Published (Approved)
Published: August 2020
Diamond Proposal Number(s): 15433

Abstract: Kinases represent one of the most intensively pursued groups of targets in modern-day drug discovery. Often it is desirable to achieve selective inhibition of the kinase of interest over the remaining ∼500 kinases in the human kinome. This is especially true when inhibitors are intended to be used to study the biology of the target of interest. We present a pipeline of open-source software that analyzes public domain data to repurpose compounds that have been used in previous kinase inhibitor development projects. We define the dual-specificity tyrosine-regulated kinase 1A (DYRK1A) as the kinase of interest, and by addition of a single methyl group to the chosen starting point we remove glycogen synthase kinase β (GSK3β) and cyclin-dependent kinase (CDK) inhibition. Thus, in an efficient manner we repurpose a GSK3β/CDK chemotype to deliver 8b, a highly selective DYRK1A inhibitor.

Journal Keywords: DYRK1A; polypharmacology; chemoinformatics; selectivity

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography

Added On: 17/08/2021 10:14

Documents:
acsmedchemlett.0c00279.pdf

Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)