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Danusertib (PHA-739358)

Danusertib (PHA-739358) is an Aurora inhibitor for Aurora A/B/C, Bcr-Abl, c-RET and FGFR with IC50 of 13 nM/79 nM/61 nM, 25 nM, 31 nM and 47 nM, respectively.

Catalog No.S1107

2 Reviews 2 Product Citations

: Tel: +1-832-582-8158[email protected]

Danusertib (PHA-739358) Chemical Structure
Molecular Weight: 474.55

Validation & Quality Control

Product Citations(2)

Biochem Pharmacol, 2012, 83(4), 452-461

J Pharmacol Exp Ther, 2012, 343(3):617-27

Customer Reviews(2) in vivo invitation

Quality Control & MSDS

Related Compound Libraries

Danusertib (PHA-739358) is available in the following compound libraries:

Cambridge Cancer Compound Library(96-well) Chemical Library (96-well) Inhibitor Library (96-well) Kinase Inhibitor Library (96-well) Stem Cell Small Molecule Compound Library (96-well)

Product Information

Compare Aurora Kinase Inhibitors

Research Area
Research Area
Danusertib (PHA-739358) Mechanism
Danusertib (PHA-739358) Mechanism
Aurora kinase A, also known as Aurora-2, is associated with centrosome maturation and separation and thereby regulates spindle assembly and stability. Aurora kinase A contains an N-terminal domain, a protein kinase domain and a short C-terminal domain. Like other protein kinases, the catalytic domain of Aurora kinases A is conserved, while the N-terminal domain of Aurora A is less conserved, which determines selectivity during protein-protein interactions. ^[1]
Danusertib is a small-molecule 3-aminopyrazole derivative. The crystal structure indicates that Danusertib targets the ATP pocket of protein kinases. Specifically, the NH2-C-N-NH pattern of the 3-aminopyrazole moiety is stereochemically well suited to form hydrogen bonding interactions with the kinase hinge region of the ATP pocket. And the terminal benzyl group and the amino nitrogen of Lys162 is within hydrogen-bonding distance of the oxygen of the pro-R methoxy substituent. Danusertib, binding to the target with the best balance, results in the inhibition of autophosphorylation in position Thr288, and Aurora-2 activity. ^[2]
References
[1] Bolanos-Garcia VM. Int J Biochem Cell Biol. 2005, 37(8), 1572-1577.
[2] Fancelli D, et al. J Med Chem. 2006, 49(24), 7247-7251.
Dr. Antonino Maria Sparta demonstrates a breakthrough in leukemia research by utilizing two inhibitors produced by Selleck Chemicals.

Cat.No.	Product Name	Solubility (25°C)
S1133	MLN8237 (Alisertib)	<1 mg/mL	1 mg/mL	<1 mg/mL
S1147	Barasertib (AZD1152-HQPA)	<1 mg/mL	102 mg/mL	3 mg/mL
S1048	VX-680 (MK-0457, Tozasertib)	<1 mg/mL	93 mg/mL	<1 mg/mL
S1107	Danusertib (PHA-739358)	<1 mg/mL	95 mg/mL	<1 mg/mL
S1103	ZM-447439	<1 mg/mL	103 mg/mL	<1 mg/mL
S1249	JNJ-7706621	<1 mg/mL	79 mg/mL	<1 mg/mL
S1100	MLN8054	<1 mg/mL	95 mg/mL	<1 mg/mL
S1134	AT9283	<1 mg/mL	76 mg/mL	38 mg/mL
S2158	KW 2449	<1 mg/mL	67 mg/mL	67 mg/mL
S1529	Hesperadin	<1 mg/mL	103 mg/mL	<1 mg/mL
S2770	MK-5108 (VX-689)	<1 mg/mL	92 mg/mL	<1 mg/mL
S1181	ENMD-2076	1 mg/mL	105 mg/mL	<1 mg/mL
S2725	PF-03814735	<1 mg/mL	0.4 mg/mL	<1 mg/mL
S2740	GSK1070916	<1 mg/mL	102 mg/mL	102 mg/mL
S1154	SNS-314 Mesylate	6 mg/mL	105 mg/mL	<1 mg/mL
S1171	CYC116	<1 mg/mL	24 mg/mL	<1 mg/mL
S1451	Aurora A Inhibitor I	<1 mg/mL	118 mg/mL	<1 mg/mL
S2719	AMG 900	<1 mg/mL	100 mg/mL	<1 mg/mL
S1454	PHA-680632	<1 mg/mL	100 mg/mL	<1 mg/mL
S1519	CCT129202	<1 mg/mL	3 mg/mL	<1 mg/mL
S2718	TAK-901	<1 mg/mL	101 mg/mL	<1 mg/mL
S2744	CCT137690	<1 mg/mL	4 mg/mL	<1 mg/mL

Product Description

Biological Activity Protocol Chemical Information Customer Reviews Product Citations Tech Support & FAQs

Biological Activity

Description	Danusertib (PHA-739358) is an Aurora inhibitor for Aurora A/B/C, Bcr-Abl, c-RET and FGFR with IC50 of 13 nM/79 nM/61 nM, 25 nM, 31 nM and 47 nM, respectively.
Targets	Aurora A/B/C	Bcr-Abl	c-RET	FGFR
IC50	13 nM/79 nM/61 nM	25nM	31 nM ^[1]	47 nM ^[2]
In vitro	Danusertib inhibits the activities of other kinases such as FGFR1, Abl, Ret and Trka, with IC50 of 47 nM, 25 nM, 31 nM and 31 nM, respectively. In a cell assay, after treatment of wild-type and p53-deficient MEFs with Danusertib, the wild-type cells undergo an arrest in mitosis (4N) that is maintained for up to 48 h. The p53-deficient cells on the other hand do not arrest at the 4N DNA stage, but continues with additional rounds of DNA synthesis to become >8N. Treatment with Danusertib results in an increase in p53 protein levels and an associated increase in p21 protein, which is known to be transcriptionally regulated by p53. ^[1] Increasing concentrations of Danusertib produces a dose-dependent reduction of cell growth after 48 hours in BCR-ABL-positive (K562, BV173) and BCR-ABL-negative (HL60) cells. ^[3]
In vivo	Administration of 25 mg/kg Danusertib (b.d. i.v.) to HL-60 xenograft rats results in 75% inhibition of tumor growth with complete regression in one animal. Danusertib results in biomarker modulation accompanied by inhibition of tumor growth. This is compatible with an expected mechanism of action of aurora kinase inhibition. ^[1] Danusertib significantly inhibits proliferation of K562 cells and virtually suppressed tumor growth during the 10-day treatment period. ^[3]
Clinical Trials	Danusertib is currently in a Phase II clinical trial in the treatment of leukemia.
Features

Protocol(Only for Reference)

Kinase Assay: ^[1]

Biochemical kinase Assays	The K_m values for ATP and the specific substrate are initially determined, and each assay is then run at optimized ATP (2K_m) and substrate (5K_m) concentrations. This setting enabled direct comparison of IC50 values of Danusertib across the applied kinase selectivity screening panel for the evaluation of the selectivity profile.

Cell Assay: ^[3]

Cell lines	CD34⁺ cells
Concentrations	5 μM
Incubation Time	5 days
Method	For short-term expansion assays, 1 × 10³ CD34⁺ cells are plated in triplicates in 96-well plates containing 100 μL of serum-free medium per well supplemented with human stem-cell factor (100 ng/mL), human Flt-3 Ligand (100 ng/mL), human thrombopoietin (50 ng/mL), human interleukin-3 and -6 (IL-3 and IL-6, respectively, both 20 ng/mL), and granulocyte colony-stimulating factor (20 ng/mL) along with Danusertib at the indicated concentrations. After 5 days, an additional 100 μL of cytokine and Danusertib containing medium are added. Cell numbers within each individual well are estimated on days 3, 6, and 9 or on days 3, 6, and 12 for healthy donor samples.

Animal Study: ^[3]

Animal Models	Female SCID mice
Formulation	In DMSO
Dosages	15 mg/kg
Administration	Intraperitoneally

References

Chemical Information

Download Danusertib (PHA-739358) SDF

Molecular Weight (MW)	474.55
Formula	C₂₆H₃₀N₆O₃
CAS No.	827318-97-8
Synonyms	N/A

Solubility (25°C) DMSO 95 mg/mL Water <1 mg/mL Ethanol <1 mg/mL
Storage	2 years -20°CPowder
	2 weeks4°Cin DMSO
	6 months-80°Cin DMSO

Chemical Name	(R)-N-(5-(2-methoxy-2-phenylacetyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide

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Research Area

Customer Reviews (2)

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Rating

Source

Dr. Yong-Weon Yi from Georgetown University Medical Center. Danusertib (PHA-739358) purchased from Selleck

Method

MTT assays

Cell Lines

MDA-MB-231 cells

Concentrations

0.01-10 μM

Incubation Time

72 h

Results

PHA-739358 decreased the viability of MDA-MB-231 cells in a dose-dependent manner.

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Rating

Source

Dr. Zhang of Tianjin Medical University. Danusertib (PHA-739358) purchased from Selleck

Method

Western blot

Cell Lines

Concentrations

0-10 μM

Incubation Time

Results

PHA739358 treatment resulted in a reduction of Histone H3 and Aurora A/B/C phosphorylation.

Product Citations (2)

Kinome-wide siRNA screening identifies molecular targets mediating the sensitivity of pancreatic cancer cells to Aurora kinase inhibitors. [Xie L, et al. Biochem Pharmacol 2012;83(4), 452-461]
PubMed: 22100984
Preclinical characterization of ABT-348, a kinase inhibitor targeting the aurora, vascular endothelial growth factor receptor/platelet-derived growth factor receptor, and Src kinase families. [Glaser KB, et al. J Pharmacol Exp Ther 2012;343(3):617-27]
PubMed: 22935731

Tech Support & FAQs

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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VX-680 (MK-0457, Tozasertib)

VX-680 (MK-0457, Tozasertib) is a pan-Aurora inhibitor of Aurora A, Aurora B and Aurora C with K_i^app of 0.6 nM, 18 nM and 4.6 nM, respectively.
Brivanib (BMS-540215)

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MLN8054

MLN8054 is a potent and selective inhibitor of Aurora A with IC50 of 4 nM.
ZM-447439

ZM-447439 is a selective and ATP-competitive inhibitor for Aurora A and Aurora B with IC50 of 110 nM and 130 nM, respectively.
MLN8237 (Alisertib)

MLN8237 (Alisertib) is a selective Aurora A inhibitor with IC50 of 1.2 nM.
AT9283

AT9283 is a potent pan-Aurora inhibitor for Aurora A, Aurora B, JAK3, JAK2 and Abl with IC50 of 3 nM, 3 nM, 1.1 nM, 1.2 nM and 4 nM, respectively.
Brivanib alaninate (BMS-582664)

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Danusertib (PHA-739358)