Hesperadin
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MedKoo CAT#: 201466

CAS#: 422513-13-1 (free base)

Description: Hesperadin is an inhibitor of human Aurora B, which can prevent the phosphorylation of substrate with IC(50) of 40 nM. Growth of cultured bloodstream forms was also sensitive to Hesperadin (IC(50) of 50 nM). Hesperadin blocked nuclear division and cytokinesis but not other aspects of the cell cycle. Consequently, growth arrested cells accumulated multiple kinetoplasts, flagella and nucleoli, similar to the effects of RNAi-dependent knockdown of TbAUK1 in cultured bloodstream forms cells. Molecular models predicted high-affinity binding of Hesperadin to both conserved and novel sites in TbAUK1. Collectively, these data demonstrate that cell cycle progression is essential for infections with T. brucei and that parasite Aurora kinases can be targeted with small-molecule inhibitors. (See: Mol Microbiol. 2009 Apr;72(2):442-58. or http://www.ncbi.nlm.nih.gov/pubmed/19320832).


Chemical Structure

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Hesperadin
CAS# 422513-13-1 (free base)

Theoretical Analysis

MedKoo Cat#: 201466
Name: Hesperadin
CAS#: 422513-13-1 (free base)
Chemical Formula: C29H32N4O3S
Exact Mass: 516.21951
Molecular Weight: 516.65
Elemental Analysis: C, 67.42; H, 6.24; N, 10.84; O, 9.29; S, 6.21

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Related CAS #: 422513-13-1 (free base); unknown (HCl)    

Synonym: Hesperadin; Hesperadine.

IUPAC/Chemical Name: (Z)-N-(2-oxo-3-(phenyl((4-(piperidin-1-ylmethyl)phenyl)amino)methylene)indolin-5-yl)ethanesulfonamide

InChi Key: GLDSKRNGVVYJAB-DQSJHHFOSA-N

InChi Code: InChI=1S/C29H32N4O3S/c1-2-37(35,36)32-24-15-16-26-25(19-24)27(29(34)31-26)28(22-9-5-3-6-10-22)30-23-13-11-21(12-14-23)20-33-17-7-4-8-18-33/h3,5-6,9-16,19,30,32H,2,4,7-8,17-18,20H2,1H3,(H,31,34)/b28-27-

SMILES Code: CCS(=O)(NC1=CC2=C(NC(/C2=C(C3=CC=CC=C3)\NC4=CC=C(CN5CCCCC5)C=C4)=O)C=C1)=O

Appearance: white solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Hesperadin is an ATP competitive indolinone inhibitor of Aurora A and B. Hesperadin inhibits Aurora B with an IC50 of 250 nM.
In vitro activity: After 24 hr exposure of BF cultures to 100 nM Hesperadin, cells contained a multi-lobed nucleus, numerous kDNA and numerous flagella (Fig. 6C, panels c-d); a pattern that phenocopied the loss of TbAUK1 with RNAi. The changes in cell population were quantified (Fig. 6B, right panel). In a wild-type BF population, approximately 60% of cells are in the 1N1K configuration, defined by a single nucleus (N) and a single kinetoplast (K). Within 24 hr of TbAUK1 depletion with RNAi, 1N1K cells declined to 8% of the population, while cells with the unusual configuration of more than 3K and an indeterminate number of nuclei (XN; K>3) increased to 81% of the population. After 24 hr exposure to 200 nM Hesperadin, cells with a 1N1K configuration dropped to 28% of the population, while cells with XN; K>3 increased to 25% of the population. Within 48 hr, cells with a XN; K>3 configuration increased to 48% of the population (Fig. 6C, right panel). Reference: Mol Microbiol. 2009 Apr;72(2):442-58. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19320832/
In vivo activity: It was confirmed that hesperadin administration for ICH mice significantly improved edema and alleviated neurological deficits at 12 h after ICH compared to the ICH group. MST4 expression in ICH mice treated with hesperadin was significantly lower than ICH mice, which proved the potential of hesperadin as an MST4 inhibitor. It was found that hesperadin is neuroprotective, which could ameliorate brain edema and behavioral deficits after experimental ICH in mice. In this study, hesperadin was confirmed to show a neuroprotective effect and can improve brain edema and neurofunction deficits in ICH mice. Reference: Behav Neurol. 2020 Feb 3;2020:2476861. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/32089749/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 100.0 193.55

Preparing Stock Solutions

The following data is based on the product molecular weight 516.65 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
In vitro protocol: 1. Jetton N, Rothberg KG, Hubbard JG, Wise J, Li Y, Ball HL, Ruben L. The cell cycle as a therapeutic target against Trypanosoma brucei: Hesperadin inhibits Aurora kinase-1 and blocks mitotic progression in bloodstream forms. Mol Microbiol. 2009 Apr;72(2):442-58. doi: 10.1111/j.1365-2958.2009.06657.x. Epub 2009 Mar 6. PMID: 19320832; PMCID: PMC2697958.
In vivo protocol: 1. Wu X, Wu J, Hu W, Wang Q, Liu H, Chu Z, Lv K, Xu Y. MST4 Kinase Inhibitor Hesperadin Attenuates Autophagy and Behavioral Disorder via the MST4/AKT Pathway in Intracerebral Hemorrhage Mice. Behav Neurol. 2020 Feb 3;2020:2476861. doi: 10.1155/2020/2476861. PMID: 32089749; PMCID: PMC7023841.

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1: Jetton N, Rothberg KG, Hubbard JG, Wise J, Li Y, Ball HL, Ruben L. The cell cycle as a therapeutic target against Trypanosoma brucei: Hesperadin inhibits Aurora kinase-1 and blocks mitotic progression in bloodstream forms. Mol Microbiol. 2009 Apr;72(2):442-58. doi: 10.1111/j.1365-2958.2009.06657.x. Epub 2009 Mar 6. PubMed PMID: 19320832; PubMed Central PMCID: PMC2697958.

2: Ladygina NG, Latsis RV, Yen T. [Effect of the pharmacological agent hesperadin on breast and prostate tumor cultured cells]. Biomed Khim. 2005 Mar-Apr;51(2):170-6. Russian. PubMed PMID: 15945350.

3: Sessa F, Mapelli M, Ciferri C, Tarricone C, Areces LB, Schneider TR, Stukenberg PT, Musacchio A. Mechanism of Aurora B activation by INCENP and inhibition by hesperadin. Mol Cell. 2005 Apr 29;18(3):379-91. PubMed PMID: 15866179.

4: Hauf S, Cole RW, LaTerra S, Zimmer C, Schnapp G, Walter R, Heckel A, van Meel J, Rieder CL, Peters JM. The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore-microtubule attachment and in maintaining the spindle assembly checkpoint. J Cell Biol. 2003 Apr 28;161(2):281-94. Epub 2003 Apr 21. PubMed PMID: 12707311; PubMed Central PMCID: PMC2172906.



Additional Information