Reversine

IC50: 150, 500 and 400 nM for Aurora Kinase A, B and C respectively

Reversine is a novel Aurora kinases inhibitor. Aurora kinases are serine/threonine kinases playing a key role in mitotic regulation. Aurora A kinase resides at spindle poles during mitosis and is implicated in the control of centrosome maturation, duplication, and separation. Aurora B is part of a chromosome passenger complex and is implicated directly in the control of microtubule kinetochore attachment. Aurora kinases have emerged as valuable targets in cancer therapy.

In vitro: Reversine could be used to induce dedifferentiation of murine myoblasts. Previous reports also showed that reversine had a role in regeneration. Moreover, a recent report indicated reversine had anti-tumor capabilities for a myeloma cell line, as demonstrated by that reversine could suppress the expression of cell cycle related proteins Aurora kinase A and Aurora kinase B [1].

In vivo: The effects of reversine on tumor weight and volume were assessed using a murine model of cervical cancer with U14 cells, separately or combined with aspirin. The inhibition rate of cells in the combination group significantly increased; moreover, such combination could synergistically inhibit the proliferation of five cervical cancer cell lines. In the mouse model, tumor weight and volume of cervical cancer bearing mice were more reduced [1].

Clinical trial: N/A

Reference:
[1] Qin HX,Yang J,Cui HK,Li SP,Zhang W,Ding XL,Xia YH.  Synergistic antitumor activity of reversine combined with aspirin in cervical carcinoma in vitro and in vivo. Cytotechnology.2013 Aug;65(4):643-53.

Structural basis of reversine selectivity in inhibiting Mps1 more potently than aurora B kinase.[Pubmed:27699881]

Proteins. 2016 Dec;84(12):1761-1766.

Monopolar spindle 1 (Mps1, also known as TTK) is a protein kinase crucial for ensuring that cell division progresses to anaphase only after all chromosomes are connected to spindle microtubules. Incomplete chromosomal attachment leads to abnormal chromosome counts in the daughter cells (aneuploidy), a condition common in many solid cancers. Therefore Mps1 is an established target in cancer therapy. Mps1 kinase inhibitors include Reversine (2-(4-morpholinoanilino)-6-cyclohexylaminopurine), a promiscuous compound first recognized as an inhibitor of the Aurora B mitotic kinase. Here, we present the 3.0-A resolution crystal structure of the Mps1 kinase domain bound to Reversine. Structural comparison of Reversine bound to Mps1 and Aurora B, indicates a similar binding pose for the purine moiety of Reversine making three conserved hydrogen bonds to the protein main chain, explaining the observed promiscuity of this inhibitor. The cyclohexyl and morpholinoaniline moieties of Reversine however, have more extensive contacts with the protein in Mps1 than in Aurora B. This is reflected both in structure-based docking energy calculations, and in new experimental data we present here, that both confirm that the affinity of Reversine towards Mps1 is about two orders of magnitude higher than towards Aurora B. Thus, our data provides detailed structural understanding of the existing literature that argues Reversine inhibits Mps1 more efficiently than Aurora B based on biochemical and in-cell assays. Proteins 2016; 84:1761-1766. (c) 2016 Wiley Periodicals, Inc.

Reversine triggers mitotic catastrophe and apoptosis in K562 cells.[Pubmed:27447890]

Leuk Res. 2016 Sep;48:26-31.

Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm of the hematopoietic stem cell characterized by presence of the oncoprotein BCR-ABL1, which have constitutive tyrosine kinase activity. BCR-ABL1 activation induces aurora kinase A (AURKA) and aurora kinase B (AURKB) expression, which are serine-threonine kinases that play an important function in chromosome alignment, segregation and cytokinesis during mitosis. Acquisition of resistance to tyrosine kinase inhibitors has emerged as a problem for CML patients and the identification of novel targets with an important contribution for CML phenotype is of interest. In the present study, we explored the cellular effects of Reversine, an AURKA and AURKB inhibitor, in the BCR-ABL1+ K562 cells. Our results indicate that Reversine reduces AURKA and AURKB expression, leads to reduction of cell viability and increased apoptosis in a dose- and time-dependent manner, as well as, induces mitotic catastrophe in K562 cells. Our preclinical study establishes that Reversine presents an effective antileukemia activity against K562 cells and provide new insights on anticancer opportunities for CML.

Effect of reversine on cell cycle, apoptosis, and activation of hepatic stellate cells.[Pubmed:27734224]

Mol Cell Biochem. 2016 Dec;423(1-2):9-20.

Experimental and clinical evidence show that liver fibrosis is potentially reversible. Hepatic stellate cells (HSCs) play a key role in the development of liver fibrosis. Some studies have shown that Reversine could induce cell apoptosis. We attempted to elucidate the effect of Reversine on cell cycle, apoptosis, and activation of HSCs. Data showed that Reversine induced morphological changes in HSCs, inhibited cell proliferation, and induced cell-cycle arrest at the G2/M phase. Reversine induced cell apoptosis through caspase-dependent and mitochondria-dependent pathways. Reversine inhibited the activation of HSCs through TGF-beta signaling pathway and degraded extracellular matrix protein collagen-I. The decreased TIMP1 and TGF-beta1 proteins promoted fibrosis reversion. Reversine might be a promising drug for liver fibrosis reversion because it induces HSCs apoptosis, restrains cell proliferation, reduces HSCs activation, and degrades extracellular matrix in vitro.

Reversine Induced Multinucleated Cells, Cell Apoptosis and Autophagy in Human Non-Small Cell Lung Cancer Cells.[Pubmed:27385117]

PLoS One. 2016 Jul 6;11(7):e0158587.

Reversine, an A3 adenosine receptor antagonist, has been shown to induce differentiated myogenic-lineage committed cells to become multipotent mesenchymal progenitor cells. We and others have reported that Reversine has an effect on human tumor suppression. This study revealed anti-tumor effects of Reversine on proliferation, apoptosis and autophagy induction in human non-small cell lung cancer cells. Treatment of these cells with Reversine suppressed cell growth in a time- and dosage-dependent manner. Moreover, polyploidy occurred after Reversine treatment. In addition, caspase-dependent apoptosis and activation of autophagy by Reversine in a dosage-dependent manner were also observed. We demonstrated in this study that Reversine contributes to growth inhibition, apoptosis and autophagy induction in human lung cancer cells. Therefore, Reversine used as a potential therapeutic agent for human lung cancer is worthy of further investigation.

Reversine is a novel class of ATP-competitive Aurora kinase inhibitor with IC50s of 400, 500 and 400 nM for Aurora A, Aurora B and Aurora C, respectively.

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