MLN8054 and Alisertib (MLN8237): Discovery of Selective Oral Aurora A Inhibitors

Sells, Todd B.; Chau, Ryan; Ecsedy, Jeffrey; Gershman, Rachel E.; Hoar, Kara M.; Huck, Jessica J.; Janowick, David A.; Kadambi, Vivek J.; Leroy, Patrick; Stirling, Matthew; Stroud, Stephen G.; Vos, Tricia J.; Weatherhead, Gabriel S.; Wysong, Deborah R.; Zhang, Mengkun; Balani, Suresh K.; Bolen, Joseph B.; Manfredi, Mark; Claiborne, Christopher F.

doi:10.1021/ml500409n

Cited by 82 publications

(55 citation statements)

References 17 publications

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“…Interestingly, MLN8054 contains a benzodiazepine core scaffold; however, a small structural change in the periphery of the molecule abrogated GABA A α-1 benzodiazepine binding and clinical incidence of somnolence in the follow-on candidate alisertib MLN8237 (Figure 5D), further emphasizing the subtlety of fine-tuning specific ligand-protein interactions (Sells et al., 2015). …”

Section: Main Textmentioning

confidence: 98%

Choose and Use Your Chemical Probe Wisely to Explore Cancer Biology

2017

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Small-molecule chemical probes or tools have become progressively more important in recent years as valuable reagents to investigate fundamental biological mechanisms and processes causing disease, including cancer. Chemical probes have also achieved greater prominence alongside complementary biological reagents for target validation in drug discovery. However, there is evidence of widespread continuing misuse and promulgation of poor-quality and insufficiently selective chemical probes, perpetuating a worrisome and misleading pollution of the scientific literature. We discuss current challenges with the selection and use of chemical probes, and suggest how biologists can and should be more discriminating in the probes they employ.

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Section: Main Textmentioning

confidence: 98%

Choose and Use Your Chemical Probe Wisely to Explore Cancer Biology

2017

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“…Alisertib (MLN8237) inhibits Aurora-A and Aurora-B kinase with an IC50 of 1.2 nM and 396.5 nM, respectively (39,40). Alisertib displays activity in preclinical models of lung, prostate, ovarian, and lymphoma cells (41).…”

Section: Aurora Kinase Inhibitionmentioning

confidence: 99%

Recent Advances of Cell-Cycle Inhibitor Therapies for Pediatric Cancer

2017

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This review describes the pivotal roles of cell cycle and checkpoint regulators and discusses development of specific cell cycle inhibitors for therapeutic use for pediatric cancer. The mechanism of action as well as the safety and tolerability of drugs in pediatric patients, including compounds that target CDK4/CDK6 (palbociclib, ribociclib, abemaciclib), aurora kinases (AT9283 and MLN8237), Wee1 kinase (MK-1775), KSP (ispinesib) and tubulin (taxanes, vinca alkaloids), are presented. The design of mechanism-based combinations that exploit the crosstalk of signals activated by cell cycle arrest, as well as pediatric-focused drug development are critical for the advancement of drugs for rare childhood diseases.

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“…The Aurora-A kinase inhibitor Alisertib is currently being tested in phases II and III clinical trials [47]. A comprehensive phase II clinical trial recently showed promising results in treatments for advanced lung and breast cancer [48].…”

Section: Discussionmentioning

confidence: 99%

Aurora-A promotes the establishment of spindle assembly checkpoint by priming the Haspin-Aurora-B feedback loop in late G2 phase

Jiang

et al. 2017

Cell Discov

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Aurora-A kinase functions mainly in centrosome maturation, separation and spindle formation. It has also been found to be amplified or overexpressed in a range of solid tumors, which is linked with tumor progression and poor prognosis. Importantly, Aurora-A inhibitors are being studied in a number of ongoing clinical trials. However, whether and how Aurora-A has a role in the regulation of the mitotic checkpoint is controversial. Additionally, the function of nuclear-accumulated Aurora-A in late G2 phase is not clear. Here we show that knockout, inhibition or blockade of the nuclear entry of Aurora-A severely decreased the centromere localization of Aurora-B and the phosphorylation of histone H3 threonine 3 (H3T3-ph) mediated by the kinase Haspin in late G2 phase. We further reveal that nuclear-accumulated Aurora-A phosphorylates Haspin at multiple sites at its N-terminus and that this promotes H3T3-ph and the rapid recruitment to the centromere of the chromosomal passenger complex. In addition, Aurora-A facilitates the association of Aurora-B with their common substrates: Haspin and Plk1. Notably, these functions of Aurora-A are mostly independent of Plk1. Thus we demonstrate that, in late G2 and prophase, Aurora-A phosphorylates Haspin to trigger the Haspin-H3T3-ph-Aurora-B positive feedback loop that supports the timely establishment of the chromosomal passenger complex and the mitotic checkpoint before spindle assembly.

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MLN8054 and Alisertib (MLN8237): Discovery of Selective Oral Aurora A Inhibitors

Cited by 82 publications

References 17 publications

Choose and Use Your Chemical Probe Wisely to Explore Cancer Biology

Choose and Use Your Chemical Probe Wisely to Explore Cancer Biology

Recent Advances of Cell-Cycle Inhibitor Therapies for Pediatric Cancer

Aurora-A promotes the establishment of spindle assembly checkpoint by priming the Haspin-Aurora-B feedback loop in late G2 phase

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