Aurora kinase inhibitors: a patent review (2014-2020)

Jing, Xueli; Chen, Shi‐Wu

doi:10.1080/13543776.2021.1890027

Cited by 22 publications

(16 citation statements)

References 87 publications

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“…It acts as an oncogene and promotes tumorigenesis, suggesting it is a potential target for cancer treatment. Interestingly, several smallmolecule Aurora-A inhibitors have been developed in recent years with promising antitumor activity in various tumors, including thyroid cancer (9,10). Alisertib has demonstrated remarkable anticancer activities by selectively inhibiting AURKA in preclinical studies and is the most advanced drug associated with 32 clinical trials (9).…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, several smallmolecule Aurora-A inhibitors have been developed in recent years with promising antitumor activity in various tumors, including thyroid cancer (9,10). Alisertib has demonstrated remarkable anticancer activities by selectively inhibiting AURKA in preclinical studies and is the most advanced drug associated with 32 clinical trials (9). Our previous study screened a small molecule inhibitor library and revealed that Alisertib yielded a superior inhibitory effect on the proliferation of ATC cells (11).…”

Section: Introductionmentioning

confidence: 99%

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Targeting Aurora-A Inhibits Tumor Progression and Sensitizes Thyroid Carcinoma to sorafenib by decreasing PFKFB3-mediated glycolysis

Jiang

Ning

et al. 2022

Preprint

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Background Thyroid cancer (TC) is the most common endocrine tumor, amongst which anaplastic thyroid carcinoma (ATC) is the most deadly. Aurora-A usually functions as oncogenes, and its inhibitor Alisertib exerts a powerful antitumor effect in various tumors. However, the mechanism of Aurora-A in regulating TC cell energy supply remains unclear. Methods Phosphoproteome and proteome analyses and RNA-seq were performed to investigate the molecular mechanisms of Aurora-A-induced tumor cell progression, which were further verified by in vitro modulations of Aurora-A and related pathways. An immunohistochemistry assay was carried out to evaluate the relationship between Aurora-A and patient prognosis. Finally, the antitumor efficacy of the Alisertib/Sorafenib combination was assessed in vitro and in vivo. Results We demonstrated the antitumor effect of Alisertib and an association between high Aurora-A expression and shorter survival. Multi-omics data and in vitro validation data suggested that Aurora-A induced PFKFB3-mediated glycolysis to increase ATP supply, which significantly upregulated the phosphorylation of ERK and AKT. The combination of Alisertib and Sorafenib had a synergistic effect, further confirmed in xenograft models and in vitro. Conclusions We provide compelling evidence of the prognostic value of Aurora-A expression and suggest that Aurora-A upregulates PFKFB3-mediated glycolysis to enhance ATP supply and promote TC progression. Combining Alisertib with Sorafenib has huge prospects for application in treating advanced thyroid carcinoma.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeting Aurora-A Inhibits Tumor Progression and Sensitizes Thyroid Carcinoma to sorafenib by decreasing PFKFB3-mediated glycolysis

Jiang

Ning

et al. 2022

Preprint

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“…The design and development of Aurora kinases inhibitors have been widely pursued in recent years. Around 36 inhibitors with potency and selectivity towards Aurora kinases over other kinases have undergone preclinical and clinical investigations, such as VX-680, MLN8054, PHA-739358, CYC116, SNS-314 and so on 3,15,16 . However, only a handful of them have some level of subtype selectivity towards Aurora A or Aurora B.…”

Section: Introductionmentioning

confidence: 99%

Exploring the structural basis of a subtype selective inhibitor for Aurora kinase B over Aurora kinase A by molecular dynamics simulations

Zhao

Kovacs

Campbell

et al. 2022

Preprint

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As promising therapeutic targets for several types of cancers, Aurora kinases A and B share remarkably high sequence and structure similarity, which render the design of subtype selective small-molecule inhibitors challenging. Since Aurora A acts as both an oncogene and a haploinsufficient tumor suppressor, inhibiting Aurora B with highly selective inhibitors represents a less toxic anti-cancer strategy. However, the molecular mechanism governing the ligand selectivity for Aurora A over B reminds elusive. In this study, an experimentally validated ligand, Barasertib which displays 1000-fold selectivity for Aurora B over A was used as a template molecule, and the selectivity mechanism was investigated by molecular dynamics simulation and binding free energy analyses. The computed binding free energies are consistent with the experimental bioactivity of Barasertib. The major residues that contribute to ligand binding were also identified. The hinge residue Arg159, only found in Aurora B was found to contribute significantly to the binding of Aurora B, while no such binding was found in Aurora A. A highly unfavorable polar interaction with Glu181 in Aurora A hinders the ligands binding ability. These 2 interactions play a key role in the observed selectivity of Barasertib for Aurora B over A. Interestingly, the binding of partner proteins forces the aC helix and the beta sheets in the N-lobe to move inward towards the ATP binding pocket, leading to a smaller hydrophobic back pocket and unfavorable binding. Taken together, our results show how differential behavior of the ligand arises from a complex interplay of small but relevant structural differences upon binding to different kinase subtypes. The insights gained into the structural determinants of subtype selectivity will facilitate the further development of highly selective and potent inhibitors as drug candidates for cancer therapy.

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“…The localization module consists of survivin, borealin, and the N-terminal part of INCENP, whereas the enzymatic module comprises Aurora B kinase and the C-terminal part of INCENP, called the INbox. The enzymatic activity of Aurora B is essential for the regulatory functions of CPC (Kelly & Funabiki, 2009; Krenn & Musacchio, 2015; Meraldi et al , 2004) so Aurora B has been identified as an attractive target for cancer chemotherapy (Portella et al , 2011), with several inhibitors patented in the last decades (Jing & Chen, 2021).…”

Section: Introductionmentioning

confidence: 99%

The structural basis of the multi-step allosteric activation of Aurora B kinase

Sekulić

Segura-Peña

Hovet

et al. 2022

Preprint

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Aurora B, together with IN-box, the C-terminal part of INCENP, forms an enzymatic complex that ensures faithful cell division. The [Aurora B/IN-box] complex is activated by autophosphorylation in the Aurora B activation loop and in IN-box, but it is not clear how these phosphorylations activate the enzyme. We used a combination of experimental and computational studies to investigate the effects of phosphorylation on the molecular dynamics and structure of [Aurora B/IN-box]. In addition, we generated partially phosphorylated intermediates to analyze the contribution of each phosphorylation independently. We found that the dynamics of Aurora and IN-box are interconnected, and IN-box plays both positive and negative regulatory roles depending on the phosphorylation status of the enzyme complex. Phosphorylation in the activation loop of Aurora B occurs intramolecularly and prepares the enzyme complex for activation, but two phosphorylated sites are synergistically responsible for full enzyme activity.

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Aurora kinase inhibitors: a patent review (2014-2020)

Cited by 22 publications

References 87 publications

Targeting Aurora-A Inhibits Tumor Progression and Sensitizes Thyroid Carcinoma to sorafenib by decreasing PFKFB3-mediated glycolysis

Targeting Aurora-A Inhibits Tumor Progression and Sensitizes Thyroid Carcinoma to sorafenib by decreasing PFKFB3-mediated glycolysis

Exploring the structural basis of a subtype selective inhibitor for Aurora kinase B over Aurora kinase A by molecular dynamics simulations

The structural basis of the multi-step allosteric activation of Aurora B kinase

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