Novel compounds with potent CDK9 inhibitory activity for the treatment of myeloma

• Published in: Bioorganic & medicinal chemistry letters 2018-02, Vol.28 (4), p.769-773
• Main Authors: Czudor, Zsófia, Balogh, Mária, Bánhegyi, Péter, Boros, Sándor, Breza, Nóra, Dobos, Judit, Fábián, Márk, Horváth, Zoltán, Illyés, Eszter, Markó, Péter, Sipos, Anna, Szántai-Kis, Csaba, Szokol, Bálint, Őrfi, László
• Format: Article
• Language: English
• Subjects: 2,4-Disubstituted pyrimidine; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Cycle Proteins - antagonists & inhibitors; Cell Line, Tumor; Cyclin dependent kinase inhibitor; Cyclin-Dependent Kinase 9 - antagonists & inhibitors; Humans; Molecular Structure; Multiple myeloma; Multiple Myeloma - drug therapy; Polo-like kinase; Polo-Like Kinase 1; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Serine-Threonine Kinases - antagonists & inhibitors; Proto-Oncogene Proteins - antagonists & inhibitors; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.01.002

[Display omitted] Cyclin-dependent kinases (CDKs) and Polo-like kinases (PLKs) play key role in the regulation of the cell cycle. The aim of our study was originally the further development of our recently discovered polo-like kinase 1 (PLK1) inhibitors. A series of new 2,4-disubstituted pyrimidine derivatives were synthesized around the original hit, but their PLK1 inhibitory activity was very poor. However the novel compounds showed nanomolar CDK9 inhibitory activity and very good antiproliferative effect on multiple myeloma cell lines (RPMI-8226).