Danusertib (PHA-739358)

Catalog No.S1107 Batch:S110704

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Technical Data

Formula

C26H30N6O3
Molecular Weight 474.55 CAS No. 827318-97-8
Solubility (25°C)* In vitro DMSO 95 mg/mL (200.18 mM)
Water Insoluble
Ethanol Insoluble
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description 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. Danusertib induces apoptosis, cell cycle arrest, and autophagy. Phase 2.
Targets
Aurora A [1]
(Cell-free assay)		 Abl [1]
(Cell-free assay)		 RET [1]
(Cell-free assay)		 TrkA [1]
(Cell-free assay)		 FGFR1 [1]
(Cell-free assay)		 View More
13 nM 25 nM 31 nM 31 nM 47 nM
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]

Protocol (from reference)

Kinase Assay:[1]
  • 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.

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

  • Dosages

    15 mg/kg

  • Administration

    Intraperitoneally

Customer Product Validation

Data from [Data independently produced by Cancer Res, 2013, 73(20), 6310-22]

Data from [Data independently produced by Biochem Pharmacol, 2012, 83(4), 452-61]

, , Dr. Yong-Weon Yi from Georgetown University Medical Center

, , Dr. Zhang of Tianjin Medical University

Selleck's Danusertib (PHA-739358) has been cited by 49 publications

The molecular basis of Abelson kinase regulation by its αI-helix [ Elife, 2024, 12RP92324] PubMed: 38588001
Inhibition of epigenetic and cell cycle-related targets in glioblastoma cell lines reveals that onametostat reduces proliferation and viability in both normoxic and hypoxic conditions [ Sci Rep, 2024, 14(1):4303] PubMed: 38383756
Visualization strategies to aid interpretation of high-dimensional genotoxicity data [ Environ Mol Mutagen, 2024, 10.1002/em.22604] PubMed: 38757760
A biophysical framework for double-drugging kinases [ Proc Natl Acad Sci U S A, 2023, 120(34):e2304611120] PubMed: 37590418
DELs enable the development of BRET probes for target engagement studies in cells [ Cell Chem Biol, 2023, 30(8):987-998.e24] PubMed: 37490918
Combined inhibition of aurora kinases and Bcl-xL induces apoptosis through select BH3-only proteins [ J Biol Chem, 2023, 299(2):102875] PubMed: 36621626
High-throughput screen in vitro identifies dasatinib as a candidate for combinatorial treatment with HER2-targeting drugs in breast cancer [ PLoS One, 2023, 18(1):e0280507] PubMed: 36706086
A biophysical framework for double-drugging kinases [ bioRxiv, 2023, 2023.03.17.533217] PubMed: 36993258
A biophysical framework for double-drugging kinases [ bioRxiv, 2023, 10.1101/2023.03.17.533217; t] PubMed: None
Differential ABC transporter expression during hematopoiesis contributes to neutrophil-biased toxicity of Aurora kinase inhibitors [ Nat Commun, 2022, 13(1):6021] PubMed: 36224199

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SHIPPING AND STORAGE
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