Structure-guided discovery of potent and selective DYRK1A inhibitors

DOI: 10.1021/acs.jmedchem.1c00023

Authors: Csaba Weber (Servier Research Institute of Medicinal Chemistry) , Melinda Sipos (Servier Research Institute of Medicinal Chemistry) , Attila Paczal (Servier Research Institute of Medicinal Chemistry) , Balazs Balint (Servier Research Institute of Medicinal Chemistry) , Vilibald Kun (Servier Research Institute of Medicinal Chemistry) , Nicolas Foloppe (Vernalis (R&D) Ltd) , Pawel Dokurno (Vernalis (R&D) Ltd) , Andrew J. Massey (Vernalis (R&D) Ltd) , David Lee Walmsley (Vernalis (R&D) Ltd) , Roderick E. Hubbard (Vernalis (R&D) Ltd) , James Murray (Vernalis (R&D) Ltd) , Karen Benwell (Vernalis (R&D) Ltd) , Thomas Edmonds (Institut de Recherches Servier) , Didier Demarles (Technologie Servier) , Alain Bruno (Institut de Recherches Servier) , Mike Burbridge (Institut de Recherches Servier) , Francisco Cruzalegui (Institut de Recherches Servier) , Andras Kotschy (Servier Research Institute of Medicinal Chemistry)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: May 2021
Diamond Proposal Number(s): 1857 , 2103

Abstract: The kinase DYRK1A is an attractive target for drug discovery programs due to its implication in multiple diseases. Through a fragment screen, we identified a simple biaryl compound that is bound to the DYRK1A ATP site with very high efficiency, although with limited selectivity. Structure-guided optimization cycles enabled us to convert this fragment hit into potent and selective DYRK1A inhibitors. Exploiting the structural differences in DYRK1A and its close homologue DYRK2, we were able to fine-tune the selectivity of our inhibitors. Our best compounds potently inhibited DYRK1A in the cell culture and in vivo and demonstrated drug-like properties. The inhibition of DYRK1A in vivo translated into dose-dependent tumor growth inhibition in a model of ovarian carcinoma.

Journal Keywords: X-rays; Chemical structure; Inhibition; Noncovalent interactions; Selectivity

Diamond Keywords: Ovarian Cancer

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


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Other Facilities: ID29 at ESRF

Added On: 26/05/2021 08:32

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)