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Fragment-derived selective inhibitors of dual-specificity kinases DYRK1A and DYRK1B

DOI: 10.1021/acs.jmedchem.1c00024 DOI Help

Authors: David Lee Walmsley (Vernalis (R&D) Ltd) , James B. Murray (Vernalis (R&D) Ltd) , Pawel Dokurno (Vernalis (R&D) Ltd) , Andrew J. Massey (Vernalis (R&D) Ltd) , Karen Benwell (Vernalis (R&D) Ltd) , Andrea Fiumana (Vernalis (R&D) Ltd) , Nicolas Foloppe (Vernalis (R&D) Ltd) , Stuart Ray (Vernalis (R&D) Ltd) , Julia Smith (Vernalis (R&D) Ltd) , Allan E. Surgenor (Vernalis (R&D) Ltd) , Thomas Edmonds (Institut de Recherches Servier) , Didier Demarles (Technologie Servier) , Mike Burbridge (Institut de Recherches Servier) , Francisco Cruzalegui (Institut de Recherches Servier) , Andras Kotschy (Servier Research Institute of Medicinal Chemistry) , Roderick E. Hubbard (Vernalis (R&D) Ltd)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: June 2021

Open Access Open Access

Abstract: The serine/threonine kinase DYRK1A has been implicated in regulation of a variety of cellular processes associated with cancer progression, including cell cycle control, DNA damage repair, protection from apoptosis, cell differentiation, and metastasis. In addition, elevated-level DYRK1A activity has been associated with increased severity of symptoms in Down’s syndrome. A selective inhibitor of DYRK1A could therefore be of therapeutic benefit. We have used fragment and structure-based discovery methods to identify a highly selective, well-tolerated, brain-penetrant DYRK1A inhibitor which showed in vivo activity in a tumor model. The inhibitor provides a useful tool compound for further exploration of the effect of DYRK1A inhibition in models of disease.

Journal Keywords: Peptides and proteins; Crystal structure; Mixtures; Inhibition; Selectivity

Diamond Keywords: Down's Syndrome

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


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 30/06/2021 09:25

Discipline Tags:

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

Technical Tags:

Diffraction Macromolecular Crystallography (MX)