Fragment-Derived Selective Inhibitors of Dual-Specificity Kinases DYRK1A and DYRK1B

• Published in: Journal of medicinal chemistry 2021-07, Vol.64 (13), p.8971-8991
• Main Authors: Lee Walmsley, David, Murray, James B, Dokurno, Pawel, Massey, Andrew J, Benwell, Karen, Fiumana, Andrea, Foloppe, Nicolas, Ray, Stuart, Smith, Julia, Surgenor, Allan E, Edmonds, Thomas, Demarles, Didier, Burbridge, Mike, Cruzalegui, Francisco, Kotschy, Andras, Hubbard, Roderick E
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Brain Neoplasms - drug therapy; Brain Neoplasms - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Dyrk Kinases; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Mice, SCID; Models, Molecular; Molecular Structure; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - metabolism; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - metabolism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c00024

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.