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PF-03814735

PF-03814735 is a novel, potent and reversible inhibitor of both Aurora A and Aurora B with IC50 of 0.8 nM and 5 nM, respectively.

Catalog No.S2725

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

PF-03814735 Chemical Structure
Molecular Weight: 474.48

Validation & Quality Control

Quality Control & MSDS

Related Compound Libraries

PF-03814735 is available in the following compound libraries:

Chemical Library (96-well) Inhibitor Library (96-well) Kinase Inhibitor Library (96-well) Pfizer Licensed Library

Product Information

Compare Aurora Kinase Inhibitors

Research Area
Research Area
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	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 Tech Support & FAQs

Biological Activity

Description	PF-03814735 is a novel, potent and reversible inhibitor of both Aurora A and Aurora B with IC50 of 0.8 nM and 5 nM, respectively.
Targets	Aurora A	Aurora B	Flt1	FAK	TrkA
IC50	0.8 nM	5 nM	10 nM	22 nM	30 nM ^[1]
In vitro	In intact cells, the inhibitory activity of PF-03814735 on the Aurora1 and Aurora2 kinases reduces levels of phospho-Aurora1 (Thr 232, a sensitive marker of Aurora1 activity, with IC50 ~ 20 nM), phosphohistone H3 (with IC50 ~ 50 nM), and phospho-Aurora2 (with IC50 ~150 nM). PF-03814735 produces a block in cytokinesis, resulting in inhibition of cell proliferation and the formation of polyploid multinucleated cells. ^[1] A recent research indicates small cell lung cancer (SCLC) and, to a lesser extent, colon cancer lines are very sensitive to PF-03814735. The status of the Myc gene family and retinoblastoma pathway members significantly correlates with the efficacy of PF-03814735. ^[1]
In vivo	Once-daily oral dosing of ≥20 mg/kg of PF-03814735 for 10 days to mice bearing HCT-116 xenografts resulted in statistically significant and dose-dependent tumor growth inhibition of ≥50% relative to vehicle-treated mice. The inhibition is associated with a reduction in phosphorylated histone H3 levels. Significant single-agent antitumor efficacy is observed in five additional xenograft tumor models, including A2780 ovarian carcinoma, MDA-MB-231 breast carcinoma, colo-205 and SW620 colorectal carcinomas, and HL-60 acute promyelocytic leukemia. ^[1] In vivo experiments with two SCLC xenograft models confirms the sensitivity of Myc gene-driven models to PF-03814735 and a possible schedule dependence of MYC/c-Myc-driven tumors. ^[1]
Clinical Trials
Features

Protocol(Only for Reference)

Kinase Assay: ^[1]

Recombinant Kinase Assays	Aurora1 and Aurora2 proteins are produced as full-length His-tag recombinant proteins expressed in insect cells. For the Aurora2 kinase assay, phosphorylation of the substrate peptide by recombinant Aurora2 protein is assessed by a Z'-LYTE assay at 3 to 300 μM ATP and various concentrations of PF-03814735 over 60 minutes, at a substrate peptide concentration of 2 μM (biotinylated LRRWSLG, ×4). Phosphorylation is linear over this time for all conditions. For the Aurora1 kinase assay, phosphorylation of the substrate peptide by recombinant Aurora1 protein is assessed by a scintillation proximity assay in a 96-well plate format in which the incorporation of ³³P into the peptide substrate (biotinylated LRRWSLG, ×4) is measured by capturing the peptide on a streptavidin scintillation proximity assay bead.

Recombinant Kinase Assays

Aurora1 and Aurora2 proteins are produced as full-length His-tag recombinant proteins expressed in insect cells. For the Aurora2 kinase assay, phosphorylation of the substrate peptide by recombinant Aurora2 protein is assessed by a Z'-LYTE assay at 3 to 300 μM ATP and various concentrations of PF-03814735 over 60 minutes, at a substrate peptide concentration of 2 μM (biotinylated LRRWSLG, ×4). Phosphorylation is linear over this time for all conditions. For the Aurora1 kinase assay, phosphorylation of the substrate peptide by recombinant Aurora1 protein is assessed by a scintillation proximity assay in a 96-well plate format in which the incorporation of ³³P into the peptide substrate (biotinylated LRRWSLG, ×4) is measured by capturing the peptide on a streptavidin scintillation proximity assay bead.

Cell Assay: ^[1]

Cell lines	HCT-116 cell
Concentrations	300 nM
Incubation Time	4, 8, 12, 24, 48, or 72 hours
Method	Cell lines are grown in appropriate media and evaluated after 48 h of exposure to either PF-03814735 or vehicle, followed by cell number determination in a Coulter Counter. Proliferation (as measured by an increase in cell number) is expressed as a percent of untreated controls. To evaluate the PF-03814735 exposure time required for antiproliferative activity, HL-60 cell cultures are cultured in RPMI medium supplemented with 15% heat-inactivated fetal bovine serum and exposed to various PF-03814735 concentrations for 4, 8, 12, 24, and 48 hours, followed by a washout step and incubation with growth media without PF-03814735 for the remainder of the 72-h assay period. Continuous exposure to PF-03814735 for 72 hours is also evaluated. Cell counts are determined by a Coulter Counter.

Animal Study: ^[1]

Animal Models	HCT116 tumors are implanted s.c. on the right flank of nude mice.
Formulation	PF-03814735 is formulated as a solution in cremophor EL [cremophor/ethanol/0.9% saline (12.5%/12.5%/75%)].
Dosages	10, 20, 30 mg/kg
Administration	Administered orally

References

Chemical Information

Download PF-03814735 SDF

Molecular Weight (MW)	474.48
Formula	C₂₃H₂₅F₃N₆O₂
CAS No.	942487-16-3
Synonyms	N/A

Solubility (25°C) DMSO 0.4 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	Acetamide, N-[2-[(1S,4R)-6-[[4-(cyclobutylamino)-5-(trifluoromethyl)-2-pyrimidinyl]amino]-1,2,3,4-tetrahydronaphthalen-1,4-imin-9-yl]-2-oxoethyl]-

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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.
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.
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.
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.
Barasertib (AZD1152-HQPA)

AZD1152-HQPA (Barasertib) is a highly selective Aurora B inhibitor with IC50 of 0.37 nM.
SNS-314

SNS-314 Mesylate is a potent and selective inhibitor of Aurora A, Aurora B and Aurora C with IC50 of 9 nM, 31 nM, and 3.4 nM, respectively.
CYC116

CYC116 is a potent inhibitor of Aurora A/B and VEGFR with K_i of 8.0 nM/9.2 nM and 44 nM, respectively.
ENMD-2076

ENMD-2076 is a selective inhibitor of Aurora A and Aurora B with IC50 of 14 nM and 350 nM and also inhibits Flt3, Flt4 and VEGFR2 with IC50 of 1.86 nM/15.9 nM and 58.2 nM, respectively.

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PF-03814735