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

Zsófia Czudor; Mária Balogh; Péter Bánhegyi; Sándor Boros; Nóra Breza; Judit Dobos; Márk Fábián; Zoltán Horváth; Eszter Illyés; Péter Markó; Anna Sipos; Csaba Szántai-Kis; Bálint Szokol; László Őrfi

doi:10.1016/j.bmcl.2018.01.002

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

Bioorg Med Chem Lett. 2018 Feb 15;28(4):769-773. doi: 10.1016/j.bmcl.2018.01.002. Epub 2018 Jan 2.

Affiliations

¹ Department of Pharmaceutical Chemistry, Semmelweis University, Hőgyes Endre u. 9, 1092 Budapest, Hungary.
² Vichem Chemie Research Ltd., Herman Ottó u. 15., 1022 Budapest, Hungary.
³ Department of Pharmaceutical Chemistry, Semmelweis University, Hőgyes Endre u. 9, 1092 Budapest, Hungary; Vichem Chemie Research Ltd., Herman Ottó u. 15., 1022 Budapest, Hungary. Electronic address: orfi.laszlo@pharma.semmelweis-univ.hu.

PMID: 29329658
DOI: 10.1016/j.bmcl.2018.01.002

Abstract

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).

Keywords: 2,4-Disubstituted pyrimidine; Cyclin dependent kinase inhibitor; Multiple myeloma; Polo-like kinase.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Cycle Proteins / antagonists & inhibitors
Cell Line, Tumor
Cyclin-Dependent Kinase 9 / antagonists & inhibitors*
Humans
Molecular Structure
Multiple Myeloma / drug therapy*
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

Substances

Antineoplastic Agents
Cell Cycle Proteins
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Pyrimidines
Protein Serine-Threonine Kinases
CDK9 protein, human
Cyclin-Dependent Kinase 9