Dual Aurora A and JAK2 kinase blockade effectively suppresses malignant transformation

Yang, Hua; Lawrence, Harshani R.; Kazi, Aslamuzzaman; Gevariya, Harsukh; Patel, Ronil A.; Luo, Yunting; Rix, Uwe; Schönbrunn, E.; Sebti, Saı̈d M.

doi:10.18632/oncotarget.1615

Cited by 19 publications

(21 citation statements)

References 53 publications

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“…As expected, Derrone reduced the phosphorylation of histone H3 on ser10, a natural substrate of Aurora B that is used as an indicator of Aurora B inhibition. 13) This compound prevented the proliferation of 4 cancer cell lines, impaired the mitotic spindle checkpoint, and induced formation of hyperploid cells called endoreduplication. These phenomena were based on a process termed "mitotic slippage," which can be induced by anti-mitotic drugs that inhibit microtubule organization and Aurora kinases.…”

Section: Discussionmentioning

confidence: 99%

“…4,5,10,11) The phosphorylation of histone H3 by Aurora B bears on chromosomes condensation and might serve as "ready production label," which is used to mark chromosome in such a way that the cell can progress from metaphase to anaphase. [10][11][12][13] The three members of human Aurora kinases are overexpressed in several human cancers such as breast, bladder, colon, ovarian, and pancreatic cancer. A strong correlation between the overexpression of Aurora kinases A and B and cell transformation and tumorigenesis has been mentioned in several research articles.…”

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confidence: 99%

“…A strong correlation between the overexpression of Aurora kinases A and B and cell transformation and tumorigenesis has been mentioned in several research articles. [14][15][16][17] Overexpression of the centrosomal protein Aurora A is related to poor prognosis in epithelial ovarian cancer patients. Aurora B expression increases in correlation with advanced stages of colorectal cancer, and its overexpression induces metastasis.…”

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confidence: 99%

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<i>In Vitro</i> Characterization of Derrone as an Aurora Kinase Inhibitor

Nhung

Phuong²,

Nguyen

et al. 2016

Biological & Pharmaceutical Bulletin

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Among mitotic kinases, Aurora kinases are the most widely studied, since their expression is restricted to mitosis. They play a key role in chromosome segregation and cell polyploidy. Aurora kinases are important therapeutic targets, and several research groups have directed their efforts toward the identification of kinase inhibitors. The aim of this study is to screen and characterize Aurora kinase inhibitors from natural substances extracted from plants that are used in the Vietnamese pharmacopoeia. We have characterized in vitro Derrone, extracted from Erythrina orientalis L. MURR, as a novel Aurora kinase inhibitor. This compound exhibited an ability to inhibit the phosphorylation of histone H3 at ser10 both in kinase assay and at the cellular level. The compound was more effective against Aurora kinase B, with a lower IC50 value as compared to Aurora A. Moreover, it impaired the mitotic spindle checkpoint and led to endoreduplication in cancer cells, a phenomenon caused by an Aurora B inhibitor. Interestingly, using the xCelligence system and real-time cell analysis (RTCA) software, we set up a comparison of cell proliferation profiles between cancer cells treated with Derrone and VX680-a well-known Aurora kinase inhibitor-and we found that these profiles exhibited considerable similarity in cell morphology, growth, and death. Additionally, Derrone significantly inhibited the formation and growth of MCF7 tumor spheroids.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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<i>In Vitro</i> Characterization of Derrone as an Aurora Kinase Inhibitor

Nhung

Phuong²,

Nguyen

et al. 2016

Biological & Pharmaceutical Bulletin

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“…Twenty-four hours after plating the cells were exposed to different concentrations of alisertib. Cell proliferation was measured by MTT assay (ATCC, Manassas, VA) at days 1, 2, 3, 7, and 10 post exposure to alisertib and the IC50 was calculated for each xenograft line, as previously described [19]. …”

Section: Methodsmentioning

confidence: 99%

Alisertib demonstrates significant antitumor activity in bevacizumab resistant, patient derived orthotopic models of glioblastoma

et al. 2016

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Aurora A Kinase (AURKA), a member of the serine/threonine kinase family, plays a critical role in cell division, and it is widely overexpressed in a variety of tumors including glioblastoma (GBM). Alisertib (MLN8237) is an orally administered selective AURKA inhibitor with potent antiproliferative activity, currently undergoing clinical testing in different tumor types. In vitro evaluation of alisertib against the primary glioblastoma (GBM) lines GBM10, GBM6 and GBM39 showed significant antitumor activity with IC50s ranging between 30–150 nM. Orthotopic xenografts of GBM39, GBM6 and GBM10 were established by implantating 3×105 cells in the caudate nucleus of nude mice; animals were randomized to treatment with either alisertib 30 mg/kg/day or vehicle. In all three models, treatment with alisertib resulted in a statistically significant prolongation of survival (p<0.0001). Alisertib administered in these mice decreased phosphorylated, Aurora-A induced mitotic arrest, and significantly decreased histone H3 phosphorylation in tumors. The same primary glioma lines were previously characterized in orthotopic in vivo models for response to the anti-VEGF antibody bevacizumab; GBM6 and GBM39 were resistant to bevacizumab treatment. In conclusion, alisertib displays significant antitumor activity against primary GBM lines and xenografts, including patient derived GBM lines resistant to bevacizumab; these data support clinical translation in GBM.

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“…2,13,31 Recently, we reported our efforts in identifying novel and exceptionally potent Aurora A inhibitors using the bisanilinopyrimidine scaffold. 32,33 In the development of novel ACK1 inhibitors, our design process incorporated an aminopyrimidine structure as the hinge binding group (Figure 2D) and fragments of 1b , 2b , and 5 as R 1 , R 2 , and R 3 (Figure 2D) groups to create hybrid structures in a mix and match process (Figure 2). …”

Section: Introductionmentioning

confidence: 99%

Development of Novel ACK1/TNK2 Inhibitors Using a Fragment-Based Approach

Lawrence

Mahajan

Luo³

et al. 2015

J. Med. Chem.

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The tyrosine kinase ACK1, a critical signal transducer regulating survival of hormone-refractory cancers, is an important therapeutic target, for which there are no selective inhibitors in clinical trials to date. This work reports the discovery of novel and potent inhibitors for ACK1 tyrosine kinase (also known as TNK2) using an innovative fragment-based approach. Focused libraries were designed and synthesized by selecting fragments from reported ACK inhibitors to create hybrid structures in a mix and match process. The hybrid library was screened by enzyme-linked immunosorbent assay-based kinase inhibition and 33P HotSpot assays. Systematic structure–activity relationship studies led to the identification of compound (R)-9b, which shows potent in vitro (IC50 = 56 nM, n = 3, 33P HotSpot assay) and in vivo (IC50 < 2 μM, human cancer cell lines) ACK1 inhibition. Both (R)-9b and (S)-9b were stable in human plasma and displayed a long half-life (t1/2 > 6 h).

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Dual Aurora A and JAK2 kinase blockade effectively suppresses malignant transformation

Cited by 19 publications

References 53 publications

<i>In Vitro</i> Characterization of Derrone as an Aurora Kinase Inhibitor

<i>In Vitro</i> Characterization of Derrone as an Aurora Kinase Inhibitor

Alisertib demonstrates significant antitumor activity in bevacizumab resistant, patient derived orthotopic models of glioblastoma

Development of Novel ACK1/TNK2 Inhibitors Using a Fragment-Based Approach

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