Hesperadin is a synthetic small‑molecule inhibitor that selectively targets Aurora B kinase, a key regulator of chromosome alignment and segregation during mitosis. It is widely used as a research tool to study the function of Aurora kinases and the spindle assembly checkpoint in eukaryotic cells.
Chemical information
- Classification: Small‑molecule kinase inhibitor
- Molecular formula: C₁₄H₉IN₂O₃ (reported in the primary literature)
- IUPAC name: 5‑(4‑iodophenyl)‑2,4‑dihydroxy‑1H‑pyridine‑3‑carboxamide (one of several reported naming conventions)
- Physical appearance: Pale yellow solid, soluble in dimethyl sulfoxide (DMSO) and other organic solvents
Mechanism of action
Hesperadin binds to the ATP‑binding pocket of Aurora B kinase, competitively inhibiting its catalytic activity. In vitro kinase assays have shown an IC₅₀ in the low‑nanomolar range (approximately 10 nM for human Aurora B). At higher concentrations, the compound also exhibits inhibitory activity against Aurora A kinase, though with reduced potency (IC₅₀ ≈ 100 nM). Inhibition of Aurora B by hesperadin leads to premature exit from mitosis, cytokinesis defects, and chromosome mis‑segregation, phenotypes that are characteristic of Aurora B loss‑of‑function.
Biological and experimental applications
- Spindle assembly checkpoint studies: By acutely blocking Aurora B activity, hesperadin allows researchers to dissect the checkpoint signaling pathway and its dependence on kinetochore tension.
- Chromosome segregation research: Treatment of cultured cells with hesperadin produces characteristic lagging chromosomes and aneuploidy, providing a model for studying the consequences of mitotic errors.
- Drug‑target validation: Hesperadin has been employed in cell‑based screens to validate Aurora B as a therapeutic target in cancer, although the compound itself is not used clinically.
- Structure‑function analyses: Derivatives of hesperadin have been synthesized to explore structure‑activity relationships within the Aurora kinase family.
Discovery and development
Hesperadin was identified in a high‑throughput chemical screen for inhibitors of the mitotic checkpoint conducted by the laboratory of Dr. Stephen C. Harrison and collaborators. The compound was first described in detail by Hauf, S., et al. in Nature (2003) as an inhibitor that phenocopies the loss of Aurora B function. Subsequent studies refined its potency and selectivity, establishing it as a standard reagent in mitotic research.
Limitations and considerations
- Selectivity: While hesperadin is relatively selective for Aurora B, off‑target effects on other kinases have been reported at micromolar concentrations.
- Stability: The compound is stable when stored as a dry powder at –20 °C; solutions in DMSO should be used promptly to avoid degradation.
- Cell permeability: Hesperadin penetrates cultured mammalian cells efficiently, but its pharmacokinetic properties are unsuitable for in vivo therapeutic use.
References
- Hauf, S.; et al. "The small molecule inhibitor Hesperadin reveals a role for Aurora B in correcting kinetochore‑microtubule attachment errors." Nature 2003, 426, 279–283.
- Carmena, M.; et al. "Asterix and Aurora B: two sides of the same coin in mitotic regulation." Journal of Cell Science 2005, 118, 3595–3604.
- Ditchfield, C.; et al. "Aurora B–dependent kinetochore–microtubule attachment error correction is essential for mitotic fidelity." Current Biology 2008, 18, 1560–1565.
This entry reflects the current state of published scientific literature up to the knowledge cutoff date.