Development and Biological Evaluation of a Novel Aurora A Kinase Inhibitor

Abstract

STOP DIVIDING: In the quest for antitumorigenic compounds, aurora A kinase has recently emerged as a potential drug target. In this paper three novel aurora inhibitors (shown in the illustration) have been tested for their biological activity in cultured cells. One of them (TC-28) appears to be a promising specific aurora A inhibitor in vivo. The aurora kinase family groups several serine/threonine kinases with key regulatory functions during cell division. The three mammalian members, aurora A, B and C, are frequently over-expressed in human tumors and the aurora A gene is located in a genomic region frequently amplified in breast and colon cancer. All these data have fuelled the idea that aurora kinases are promising targets for anticancer therapy. Indeed some inhibitory compounds are currently being evaluated in clinical trials. However, it was recently shown that mutations in the targeted kinase can confer resistance to a broad range of inhibitors and render patients resistant to treatments. Moreover, aurora A over-expression results in increased resistance to antimitotic agents. The development of new compounds targeting aurora A is therefore highly relevant. We describe here the synthesis of three novel aurora kinase inhibitors, TC-28, TC-34 and TC-107. We report their properties as aurora inhibitors in vitro and their effect on human tissue culture cell lines. Interestingly, our results show that TC-28 has properties compatible with the specific inhibition of aurora A, in vivo.

2-Cinnamamido, 2-(3-phenylpropiolamido), and 2-(3-phenylpropanamido)benzamides: Synthesis, antiproliferative activity, and mechanism of action

“…In particular, the 5-iodo-2-aminobenzamide 2e was obtained, as reported in the literature [11], by treatment of anthranilamide 2a with iodine in an aqueous solution of sodium bicarbonate.…”

Suppression of Proinflammatory and Prosurvival Biomarkers in Oral Cancer Patients Consuming a Black Raspberry Phytochemical-Rich Troche

“…AURKA can also positively regulate NFκB activities by phosphorylating IκBα and Ras signalling via RalA phosphorylation. Evaluation of small molecule inhibitors MK8745 (60), MLN8237 (61,62), TC-28 (63), MLN8054 (47), VX680 (47) have demonstrated some efficacy in inhibiting AURKA-associated mitotic transition defects, but several have been subsequently discontinued following clinical evaluation (VX680, Phase II; MLN8054, Phase I) (64). In partnership with deregulated cell cycle checks, the loss of apoptotic control during carcinogenesis results in the inability to remove (and persistence of) genetically compromised cells.…”

A phase I study of MK-5108, an oral aurora a kinase inhibitor, administered both as monotherapy and in combination with docetaxel, in patients with advanced or refractory solid tumors

“…While toxicity-related issues precluded the attainment of anticipated therapeutic dose levels in the CT panel, there was some evidence of target engagement in the MT panel as demonstrated by PD effects in surrogate tissues. Possible future areas of research may include evaluating the effects of MK-5108 on alternative PD biomarkers, such as the expression of proliferating cell nuclear antigen, Ki67, M30 and M65 in skin and plasma samples, as well as investigating inducible mutations in the targeted protein kinases that have been previously shown to be associated with the development of AKI resistance [4, 12, 22, 23]. …”