Discovery of 2-(1H-indol-5-ylamino)-6-(2,4-difluorophenylsulfonyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (7ao) as a potent selective inhibitor of Polo like kinase 2 (PLK2)

Abstract

Several families of protein kinases have been shown to play a critical role in the regulation of cell cycle progression, particularly progression through mitosis. These kinase families include the Aurora kinases, the Mps1 gene product and the Polo Like family of protein kinases (PLKs). The PLK family consists of five members and of these, the role of PLK1 in human cancer is well documented. PLK2 (SNK), which is highly homologous to PLK1, has been shown to play a critical role in centriole duplication and is also believed to play a regulatory role in the survival pathway by physically stabilizing the TSC1/2 complex in tumor cells under hypoxic conditions. As a part of our research program, we have developed a library of novel ATP mimetic chemotypes that are cytotoxic against a panel of cancer cell lines. We show that one of these chemotypes, the 6-arylsulfonyl pyridopyrimidinones, induces apoptosis of human tumor cell lines in nanomolar concentrations. The most potent of these compounds, 7ao, was found to be a highly specific inhibitor of PLK2 when profiled against a panel of 288 wild type, 55 mutant and 12 lipid kinases. Here, we describe the synthesis, structure activity relationship, in vitro kinase specificity and biological activity of the lead compound, 7ao.

Polo-like kinases as potential targets and PLK2 as a novel biomarker for the prognosis of human glioblastoma

“…Current PLK2 inhibitors, ON1231320, has been demonstrated to be a selective repressor of PLK2, with no dampening activity against PLK1, PLK3 and PLK4. In contrast with the control group, PLK2 inhibitor treatment remarkably restrained tumor growth and there were no remarkable toxic effects in the treatment group [ 17 ]. ON1231210 is effective in different tumor cell lines, but not in non-tumorous human fibroblasts.…”

A deep tabular data learning model predicting cisplatin sensitivity identifies BCL2L1 dependency in cancer

“…Ovarian serous cystadenocarcinoma cell line SKOV3 was cultured in McCoy’s 5a supplemented with 2 mM glutamate. Selective BCL2L1 inhibitor A-1155463 [60] , potent BCL2, BCL2L1, and BCL2L2 inhibitor navitoclax [61] , selective PLK2 inhibitor ON1231320 [62] , and TCF4/β-catenin complex formation inhibitors (LF3 [63] and toxoflavin [64] ) were purchased from MedChemExpress.…”

Polo-Like Kinase 2: From Principle to Practice

“…The PLK2 specific inhibitors C2 and C21 constructed based on tetrahydropteridin effectively inhibit the growth of various human tumor cell lines in vitro ( 167 ). PLK2 specific inhibitor 7AO (ON1231320) blocks tumor cell cycle during mitosis, leading to cell apoptosis; Synergistic action with paclitaxel effectively suppressed tumor growth in vivo ( 168 ). In neurodegenerative diseases, oral administration of potent selective inhibitors of PLK2 that could cross the blood-brain barrier significantly reduces the phosphorylation of α-Syn in rat brain, providing a direction for the treatment of PD ( 117 ).…”