Danusertib (PHA-739358)

製品コードS1107 バッチS110703

化学情報

	Synonyms	N/A	Storage (From the date of receipt)	3 years -20°C powder 1 years -80°C in solvent
	化学式	C₂₆H₃₀N₆O₃
	分子量	474.55	CAS No.	827318-97-8
Solubility (25°C)*	体外	DMSO	95 mg/mL (200.18 mM)
		Ethanol	34 mg/mL (71.64 mM)
		Water	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.

溶剤液（一定の濃度）を調合する

生物活性

製品説明	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.
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]

プロトコル(参考用のみ)

キナーゼアッセイ	Biochemical kinase Assays
キナーゼアッセイ	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.
細胞アッセイ	細胞株	CD34⁺ cells
	濃度	5 μM
	反応時間	5 days
	実験の流れ	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.
動物実験	動物モデル	Female SCID mice
	投薬量	15 mg/kg
	投与方法	Intraperitoneally

参考

カスタマーフィードバック

: 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

Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：

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
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
Widespread genomic/molecular alterations of DNA helicases and their clinical/therapeutic implications across human cancer [ Biomed Pharmacother, 2022, 158:114193]	PubMed: 36586240
Combined Inhibition of Polo-Like Kinase-1 and Wee1 as a New Therapeutic Strategy to Induce Apoptotic Cell Death in Neoplastic Mast Cells [ Cancers (Basel), 2022, 14(3)738]	PubMed: 35159005

長期の保管のために-20°Cの下で製品を保ってください。

人間や獣医の診断であるか治療的な使用のためにでない。

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