Pyrido[2,3-d]pyrimidines: Discovery and preliminary SAR of a novel series of DYRK1B and DYRK1A inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2013-12, Vol.23 (24), p.6610-6615
• Main Authors: Anderson, Kevin, Chen, Yi, Chen, Zhi, Dominique, Romyr, Glenn, Kelli, He, Yang, Janson, Cheryl, Luk, Kin-Chun, Lukacs, Christine, Polonskaia, Ann, Qiao, Qi, Railkar, Aruna, Rossman, Pamela, Sun, Hongmao, Xiang, Qing, Vilenchik, Masha, Wovkulich, Peter, Zhang, Xiaolei
• Format: Article
• Language: English
• Subjects: Animals; Anti-cancer; Binding Sites; Crystallography, X-Ray; Dyrk Kinases; DYRK1A; DYRK1B; Enzyme Activation - drug effects; Half-Life; Humans; Kinase-inhibitor; Molecular Dynamics Simulation; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - metabolism; Protein Structure, Tertiary; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - metabolism; Pyrido[2,3-d]pyrimidine; Pyrimidines - chemistry; Pyrimidines - pharmacokinetics; Rats; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.10.055

DYRK1B is a kinase over-expressed in certain cancer cells (including colon, ovarian, pancreatic, etc.). Recent publications have demonstrated inhibition of DYRK1B could be an attractive target for cancer therapy. From a data-mining effort, the team has discovered analogues of pyrido[2,3-d]pyrimidines as potent enantio-selective inhibitors of DYRK1B. Cells treated with a tool compound from this series showed the same cellular effects as down regulation of DYRK1B with siRNA. Such effects are consistent with the proposed mechanism of action. Progress of the SAR study is presented.