DYRK1A and DYRK1B selective inhibitors
A Vernalis and Servier NMR fragment screen produced two series of potent, selective DYRK1A inhibitors, including the brain-penetrant tool compound 34.
The Challenge
The serine/threonine kinase DYRK1A has been implicated in the 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. Elevated DYRK1A activity has also been associated with increased severity of symptoms in Down’s syndrome. A selective inhibitor of DYRK1A could therefore be of therapeutic benefit.
Related Publications
Fragment-Derived Selective Inhibitors of Dual-Specificity Kinases DYRK1A and DYRK1B
Walmsley, D. L. et al., J. Med. Chem. 2021, 64, 8971–8991
Read on ACS PublicationsStructure-Guided Discovery of Potent and Selective DYRK1A Inhibitors
Weber, C. et al., J. Med. Chem. 2021, 64, 6745–6764
Read on ACS PublicationsThe Science
A collaboration between Vernalis Research and Servier used a ligand-observed NMR screen to identify fragments that bound competitively at the ATP site of DYRK1A. These led to two series of optimised, potent inhibitors of DYRK1A, described across two publications.
One example compound is the highly selective, well-tolerated, brain-penetrant DYRK1A inhibitor 34, which showed in vivo activity in a tumour model.
These inhibitors provide useful tool compounds for further exploration of the effect of DYRK1A inhibition in models of disease.
Structure of compound 34 bound to DYRK1A (PDB: 7A5N).
Key Takeaways
- Ligand-observed NMR screening identified fragments binding competitively at the ATP site
- Two separate optimised inhibitor series developed from those hits
- Compound 34 highly selective, well tolerated and brain-penetrant, with in vivo tumour model activity
- Delivered tool compounds for onward exploration across disease models
Service Areas
Work with us
Vernalis has collaborated with a wide range of partners to enable some of the most challenging therapeutic targets. Present and past collaborators include Servier, Pierre Fabre, Genentech and Lundbeck. Vernalis can support programs with DEL and fragment-based technologies through to establishing full drug discovery programmes for our partners.
Our track record is built on innovation and success in enabling drug discovery and identifying clinical candidates for a wide variety of therapeutic targets.
Research Director and Joint Site Lead
James Murray PhD
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