Home Cell Cycle Aurora Kinase inhibitor - Bcr-Abl inhibitor - c-RET inhibitor - FGFR inhibitor - Autophagy activator - Apoptosis related activator - Trk receptor inhibitor Danusertib (PHA-739358)

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Danusertib (PHA-739358) Aurora Kinase inhibitor

Cat.No.S1107

Danusertib (PHA-739358) is an Aurora kinase inhibitor for Aurora A/B/C with IC50 of 13 nM/79 nM/61 nM in cell-free assays, modestly potent to Abl, TrkA, c-RET and FGFR1, and less potent to Lck, VEGFR2/3, c-Kit, CDK2, etc. It induces apoptosis, cell cycle arrest, and autophagy. This compound is in Phase 2.
Danusertib (PHA-739358) Aurora Kinase inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 474.55

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Quality Control

Cell Culture, Treatment & Working Concentration

Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
A2780 cells Proliferation assay Antiproliferative activity against A2780 cells, IC50=28 nM
HCT116 cells Proliferation assay Antiproliferative activity against HCT116 cells, IC50=31 nM
human HCT116 cells Proliferation assay Antiproliferative activity against human HCT116 cells assessed as BrdU incorporation after 72 hrs, IC50=31 nM
HCT116 cells Function assay Cell cycle arrest in HCT116 cells by accumulation at G2/M phase, EC50=80 nM
MCF7 cells Proliferation assay Antiproliferative activity against MCF7 cells, IC50=80 nM
HeLa cells Proliferation assay Antiproliferative activity against HeLa cells, IC50=0.14 μM
human MOLT4 cells Cytotoxic assay Cytotoxicity against human MOLT4 cells assessed as inhibition of cell growth after 4 days by Cell Titer Blue end-point assay, EC50=0.15 μM
human HepG2 cells Cytotoxic assay Cytotoxicity against human HepG2 cells after 48 hrs by MTT assay, TC50=4 μM
human A2780 cells Proliferation assay Antiproliferative activity against human A2780 cells assessed as accumulation of 4N DNA, IC50=28 μM
HCT116 cells Function assay Inhibition of histone h3 phosphorylation in HCT116 cells by Western blot analysis
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Chemical Information, Storage & Stability

Molecular Weight 474.55 Formula

C26H30N6O3

 Storage (From the date of receipt)
CAS No. 827318-97-8 Download SDF Storage of Stock Solutions

Synonyms N/A Smiles CN1CCN(CC1)C2=CC=C(C=C2)C(=O)NC3=NNC4=C3CN(C4)C(=O)C(C5=CC=CC=C5)OC

Solubility

In vitro
Batch:

DMSO : 95 mg/mL (200.18 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Water : Insoluble

Ethanol : Insoluble

Molarity Calculator

Mass Concentration Volume Molecular Weight

In vivo
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In vivo Formulation Calculator (Clear solution)

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Working concentration: mg/ml;

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Mechanism of Action

Targets/IC50/Ki
Aurora A [1]
(Cell-free assay)
13 nM
Abl [1]
(Cell-free assay)
25 nM
RET [1]
(Cell-free assay)
31 nM
TrkA [1]
(Cell-free assay)
31 nM
FGFR1 [1]
(Cell-free assay)
47 nM
Aurora C [1]
(Cell-free assay)
61 nM
Aurora B [1]
(Cell-free assay)
79 nM
In vitro
Danusertib (PHA-739358) 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 this compound, 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 it 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]
Kinase Assay
Biochemical kinase Assays
The Km values for ATP and the specific substrate are initially determined, and each assay is then run at optimized ATP (2Km) and substrate (5Km) 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.
In vivo
Administration of 25 mg/kg S1107 to HL-60 xenograft rats results in 75% inhibition of tumor growth with complete regression in one animal. S1107 results in biomarker modulation accompanied by inhibition of tumor growth. This is compatible with an expected mechanism of action of aurora kinase inhibition. [1] S1107 significantly inhibits proliferation of K562 cells and virtually suppressed tumor growth during the 10-day treatment period. [3]
References

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