Benzo[e]pyridoindoles,  novel inhibitors of the Aurora kinases

Abstract

Aurora kinases are serine/threonine protein kinases that are involved in cancer development and are important targets for cancer therapy. By high throughput screening of a chemical library we found that benzo[e]pyridoindole derivatives inhibited Aurora kinases. The most potent compound (compound 1) was found to be an ATP competitive inhibitor, which inhibited in vitro Aurora kinases at the nanomolar range. It prevented, ex vivo, the phosphorylation of Histone H3, induced mitosis exit without chromosome segregation, known phenomena observed upon Aurora B inactivation. This compound was also shown to affect the localization of Aurora B, since in the presence of the inhibitor the enzyme was delocalized on the whole chromosomes and remained associated with the chromatin of newly formed nuclei.In addition, compound 1 inhibited the growth of different cell lines derived from different carcinoma. Its IC 50 for H358 NSCLC (Non-Small Cancer Lung Cells), the most sensitive cell line, was 145 nM. Furthermore compound 1 was found to be efficient towards multicellular tumor spheroid growth. It exhibited minimal toxicity in mice while it had some potency towards aggressive NSCLC tumors. Benzo[e]pyridoindoles represent thus a potential new lead for the development of Aurora kinase inhibitors.

Pharmacological Inhibition of LIM Kinase Stabilizes Microtubules and Inhibits Neoplastic Growth

“…Previous screening identified a class of Pyr1 structurally related compounds that often targets protein kinases (26,29). We therefore tested the ability of Pyr1 to inhibit the activity of a panel of 66 protein kinases known to be involved in the regulation of the cytoskeleton.…”

Aurora kinases orchestrate mitosis; who are the players?

“…It is established that both Aurora-A, -B kinases are autophosphorylated (Table 1A and C) and, that their accurate localizations depend on their activity (10,66,68). In the presence of inhibitors or dominant negative kinase Aurora-B localized on centromere but progressively fused on the whole chromatin as revealed by time-lapse experiments (66,68,69).…”

“…Upon such a mitotic abortion, cells are polyploid and exhibit irregular lobed nuclei (66). Therefore passenger protein inhibition prevents at least cell expansion.…”

Survivine, interprète du code histone mitotique

“…En fait, le groupe de Y. Watanabe a montré que la phosphorylation de l'histone H3-Thr3 agissait de concert avec une autre modification portée par l'histone H2A [8,9]. En effet, au cours de la mitose, la kinase Bub1 est pré-sente sur les centromères internes et phosphoryle la Ser 210 de l'histone H2A recrutant ainsi les protéines shugoshine [7].…”