Aurora Kinase Inhibitors in Oncology Clinical Trials: Current State of the Progress

Falchook, Gerald S.; Bastida, Christel C.; Kurzrock, Razelle

doi:10.1053/j.seminoncol.2015.09.022

Cited by 92 publications

(83 citation statements)

References 116 publications

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“…Dual inhibitors of these two types of kinases, such as ENMD-2076, ABT-348, and JNJ-28840172, have been reported recently to exhibit potential antitumor activities in different cancer types [31–33]. Meaningfully, ENM-2076 is currently in Phase I/II clinical trials for several types of cancer [34], which greatly encouraged the development of this type of dual inhibitors. Here we have demonstrated TY-011 exhibited a significant antitumor effect in gastric cancer xenograft model at a very low dose, and showed no observable side effects, therefore TY-011 deserves further investigation and development.…”

Section: Discussionmentioning

confidence: 99%

Antitumor activity of TY-011 against gastric cancer by inhibiting Aurora A, Aurora B and VEGFR2 kinases

Liu

Lü

Chai

et al. 2016

J Exp Clin Cancer Res

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BackgroundOverexpression of Aurora A and B has been reported in a wide range of tumor types, including gastric cancer. Anti-angiogenesis has been considered as an important therapeutic modality in advanced gastric cancer. Here we identified a novel compound TY-011 with promising antitumor activity by targeting mitotic kinases (Aurora A and B) and angiogenic receptor tyrosine kinase (VEGFR2).MethodsHTRF® KinEASE™ assay was used to detect the effect of TY-011 against Aurora A, Aurora B and VEGFR2 activities. Docking simulation study was performed to predict the binding mode of TY-011 with Aurora A and B kinases. CCK-8 assay was used to test cell growth. Cell cycle and cell apoptosis was analyzed by flow cytometry. Gastric cancer cell xenograft mouse models were used for in vivo study. TUNEL kit was used to determine the apoptosis of tumor tissues. Immunohistochemistry analysis and HUVEC tube formation assay were performed to determine the anti-angiogenesis ability. Immunofluorescence and western blot were used to test protein expression.ResultsTY-011 was identified as a potential Aurora A and B inhibitor by HTRF® KinEASE™ assay. It effectively inhibited cellular Aurora A and B activities in a concentration-dependent manner. TY-011 occupied the ATP-binding site of both Aurora A and B kinases. TY-011 demonstrated prominent inhibitory effects on proliferation of gastric cancer cells. TY-011 treatment induced an obvious accumulation of cells at G2/M phase and a modest increase of cells with >4 N DNA content, which then underwent apoptosis. Meaningfully, orally administration of TY-011 demonstrated superior efficacy against the tumor growth in gastric cancer cell xenograft, with ~90% inhibition rate and 100% tumor regression at 9 mg/kg dose, and TY-011 did not affect the body weight of mice. Interestingly, we observed that TY-011 also antagonized tumor angiogenesis by targeting VEGFR2 kinase.ConclusionsThese results indicate that TY-011 is a well-tolerated, orally active compound that targets mitosis and angiogenesis in tumor growth, and provides strong preclinical support for use as a therapeutic for human gastric cancers.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0464-2) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Antitumor activity of TY-011 against gastric cancer by inhibiting Aurora A, Aurora B and VEGFR2 kinases

Liu

Lü

Chai

et al. 2016

J Exp Clin Cancer Res

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“…Commonly used approaches for discovery and development of AKIs include structure-based drug design, especially in a fragment-based design, structure-based virtual screening, biochemical cell proliferation or enzyme inhibition assay, and rational design followed by combinatorial expansion. 17,18,[57][58][59] After discovery and identification of the first AKI ZM447439 as a potential drug for targeted therapy in cancer treatment, there have been more than 35 AKIs which are being tested in preclinical and clinical cancer treatment so far. Currently, over a dozen of AKIs are in various phases of clinical development.…”

Section: Discovery Of New Akis and Their Binding Modes With Aurka Andmentioning

confidence: 99%

“…A series of Aurora kinase inhibitors (AKIs) have been discovered and developed in a hope to inhibit AURKA, AURKB, and/or even AURKC . Some of these inhibitors, such as danusertib, are able to act as dual‐ or multiple inhibitors of Aurora kinases.…”

Section: Introductionmentioning

confidence: 99%

“…14 A series of Aurora kinase inhibitors (AKIs) have been discovered and developed in a hope to inhibit AURKA, AURKB, and/ or even AURKC. [15][16][17][18][19][20][21] Some of these inhibitors, such as danusertib, are able to act as dual-or multiple inhibitors of Aurora kinases. Alisertib, 4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5Hpyrimido [5,4-d]benzazaepin-2-yl]amino-2-methoxybenzoic acid (see Fig.…”

Section: Introductionmentioning

confidence: 99%

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An update on the pharmacokinetics and pharmacodynamics of alisertib, a selective Aurora kinase A inhibitor

Durlacher

Chen

et al. 2016

Clin Exp Pharma Physio

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SUMMARYHuman Aurora kinases, including Aurora kinase A (AURKA), B (AURKB), and C (AURKC), play an essential role in mitotic events such as monitoring of the mitotic checkpoint, creation of bipolar mitotic spindle and alignment of centrosomes on it, also regulating centrosome separation, bioorientation of chromosomes and cytokinesis. AURKA and AURKB are key regulators of mitosis and centrosome via polymerizing microfilaments and controlling chromatid segregation. In particular, AURKA plays critical roles in the regulation of mitotic entry, centrosome function, bipolar spindle assembly, and chromosome segregation. AURKA has been found to be overexpressed in various solid and haematological cancers and has been linked with poor prognosis. Its important role in cancer initiation, growth, and metastasis has brought the focus to search for potent and selective AURKA inhibitors for cancer treatment. MLN8237, also known as alisertib, is one selective AURKA inhibitor that has shown remarkable anticancer effects in preclinical studies. Alisertib exhibits favourable pharmacokinetic properties. Alisertib has generally showed good partial response rates of 4-52% and good safety profiles in Phase I and II trials when it is solely administered as well as combined with cytotoxic chemotherapeutic drugs. Recently, the multicentre, randomized Phase III study of alisertib in patients with relapsed or refractory peripheral T-cell lymphoma has been discontinued due to unsatisfactory efficacy. The low risk of side effects, accessibility, and effectiveness of alisertib makes it a new promising anticancer therapy and further mechanistic and clinical studies are warranted.

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“…In addition, Aurora B overexpression predicted worse 5‐year survival in hepatocellular carcinoma regardless of Aurora A expression status, suggesting that Aurora B could be a better therapeutic target for controlling tumor mitosis. Recently, some selective or pan‐Auroras kinase inhibitors have entered into clinical trials with promising therapeutic benefits …”

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confidence: 99%

CS2164, a novel multi‐target inhibitor against tumor angiogenesis, mitosis and chronic inflammation with anti‐tumor potency

Zhou¹,

Song²,

Li³

et al. 2017

Cancer Science

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Although inhibitors targeting tumor angiogenic pathway have provided improvement for clinical treatment in patients with various solid tumors, the still very limited anti‐cancer efficacy and acquired drug resistance demand new agents that may offer better clinical benefits. In the effort to find a small molecule potentially targeting several key pathways for tumor development, we designed, discovered and evaluated a novel multi‐kinase inhibitor, CS2164. CS2164 inhibited the angiogenesis‐related kinases (VEGFR2, VEGFR1, VEGFR3, PDGFRα and c‐Kit), mitosis‐related kinase Aurora B and chronic inflammation‐related kinase CSF‐1R in a high potency manner with the IC 50 at a single‐digit nanomolar range. Consequently, CS2164 displayed anti‐angiogenic activities through suppression of VEGFR/PDGFR phosphorylation, inhibition of ligand‐dependent cell proliferation and capillary tube formation, and prevention of vasculature formation in tumor tissues. CS2164 also showed induction of G2/M cell cycle arrest and suppression of cell proliferation in tumor tissues through the inhibition of Aurora B‐mediated H3 phosphorylation. Furthermore, CS2164 demonstrated the inhibitory effect on CSF‐1R phosphorylation that led to the suppression of ligand‐stimulated monocyte‐to‐macrophage differentiation and reduced CSF‐1R+ cells in tumor tissues. The in vivo animal efficacy studies revealed that CS2164 induced remarkable regression or complete inhibition of tumor growth at well‐tolerated oral doses in several human tumor xenograft models. Collectively, these results indicate that CS2164 is a highly selective multi‐kinase inhibitor with potent anti‐tumor activities against tumor angiogenesis, mitosis and chronic inflammation, which may provide the rationale for further clinical assessment of CS2164 as a therapeutic agent in the treatment of cancer.

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Aurora Kinase Inhibitors in Oncology Clinical Trials: Current State of the Progress

Cited by 92 publications

References 116 publications

Antitumor activity of TY-011 against gastric cancer by inhibiting Aurora A, Aurora B and VEGFR2 kinases

Antitumor activity of TY-011 against gastric cancer by inhibiting Aurora A, Aurora B and VEGFR2 kinases

An update on the pharmacokinetics and pharmacodynamics of alisertib, a selective Aurora kinase A inhibitor

CS2164, a novel multi‐target inhibitor against tumor angiogenesis, mitosis and chronic inflammation with anti‐tumor potency

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