Linsitinib (OSI-906)

製品コードS1091 バッチS109111

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	C₂₆H₂₃N₅O
	分子量	421.49	CAS No.	867160-71-2
Solubility (25°C)*	体外	DMSO	72 mg/mL (170.82 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.

溶剤液（一定の濃度）を調合する

生物活性

製品説明	Linsitinib (OSI-906) is a selective inhibitor of IGF-1R with IC50 of 35 nM in cell-free assays; modestly potent to InsR with IC50 of 75 nM, and no activity towards Abl, ALK, BTK, EGFR, FGFR1/2, PKA etc. Phase 3.
in vitro	OSI-906 inhibits IGF-1R autophosphorylation and activation of the downstream signaling proteins Akt, ERK1/2 and S6 kinase with IC50 of 0.028 to 0.13 μM. OSI-906 enables an intermediate conformation of the target protein through interactions with the C-helix. OSI-906 displays favorable metabolic stability in liver microsomes. OSI-906 fully inhibits both IR and IGF-1R phosphorylation at a concentration of 1 μM. OSI-906 inhibits proliferation of several tumor cell lines including non-small-cell lung cancer and colorectal cancer (CRC) tumor cell line with EC50 of 0.021 to 0.810 μM. ^[1]
in vivo	OSI-906 inhibits tumor growth in an IGF-1R-driven xenograft mouse model, with 100% TGI and 55% regression at a dose of 75 mg/kg and 60% TGI and no regression at a dose of 25 mg/kg. OSI-906 administration induces different elimination half-lives of itself in dog, rat and mice, the elimination half-lives are 1.18 hours, 2.64 hours and 2.14 hours, respectively. OSI-906 administration at different single dose once-daily in femal Sprague-Dawley rat and femal CD-1 mouse reveal that the V_max is not dose-proportional to OSI-906 dose. OSI-906 elevates the blood glucose levels at a dose of 25 mg/kg after 12 days administration. OSI-906 administration at a single dose of 75 mg/kg in IGF-1R-driven full-length human IGF-1R (LISN) xenograft mouse model achieve maximal inhibition of IGF-1R phosphorylation (80%) between 4 and 24 hours with plasma drug concentrations of 26.6-4.77 μM. ^[1] OSI-906 administered as a single dose of at 60 mg/kg in NCI-H292 xenografts mice inhibits uptake of glucose at 2, 4, and 24 hours post-treatment in vivo. OSI-906 inhibits the growth of tumors in NCI-H292 xenograft mouse model. ^[2]

プロトコル(参考用のみ)

キナーゼアッセイ	Protein kinase biochemical assays
キナーゼアッセイ	Protein kinase assays are either performed in-house by ELISA-based assay methods (IGF-1R, IR, EGFR and KDR) or at Upstate Inc. by a radiometric method with ATP at 100 µM concentration. In-house ELISA assays use poly(Glu:Tyr) as the substrate bound to the surface of 96-well assay plates and phosphorylation is detected using an antiphosphotyrosine antibody conjugated to horseradish peroxidase. The bound antibody is quantified using ABTS as the peroxidase substrate by measuring absorbance at 405 / 490 nm. All assays use purified recombinant kinase catalytic domains. Recombinant enzymes of human IGF-1R or EGFR are expressed as an NH2-terminal glutathione S-transferase fusion protein in insect cells and are purified in house. IC50 values are determined from the sigmoidal dose–response plot of percent inhibition versus log₁₀ compound concentration. A minimum of three measurements, performed in duplicate, are carried out with in-house assays unless otherwise indicated. OSI-906 at a concentration of 1 µM is profiled versus a panel of kinases using the ProfilerPro^TM Kinase Selectivity Assay Kit.
細胞アッセイ	細胞株	MCF7, NCI-H292, Colo-205, HT29, H358, H1703, BxPC3, A673, SW620, DU4475, HepG2 and Hepa-1, RKO 3T3/hulGF-IR and H292 cells
	濃度	0.02-0.8 μM
	反応時間	3 days
	実験の流れ	For assays of cell proliferation, cells are seeded into 96-well plates in appropriate media containing FCS 10% and incubated for 3 days in the presence of OSI-906 at various concentrations. Inhibition of cell growth is determined by luminescent quantitation of intracellular ATP content using CellTiterGlo. Data is presented as a fraction of maximal proliferation, calculated by dividing the cellular density in the presence of varying concentrations of OSI-906 by the cellular density of control cells treated with vehicle (DMSO) only.
動物実験	動物モデル	IGF-1R-driven full-length human IGF-1R (LISN) xenograft mouse model
	投薬量	25 mg / kg and 75 mg / kg
	投与方法	Orally administrated at once-daily oral dose for 14 days

参考

カスタマーフィードバック

: Data from [Cancer Res, 2013, 73, 834-843]

: Data from [Cancer Res, 2011, 71, 6773-84]

: ,

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：

Caloric restriction leads to druggable LSD1-dependent cancer stem cells expansion [ Nat Commun, 2024, 15(1):828]	PubMed: 38280853
Acinar-ductal cell rearrangement drives branching morphogenesis of the murine pancreas in an IGF/PI3K-dependent manner [ Dev Cell, 2024, 59(3):326-338.e5]	PubMed: 38237591
Insulin receptor signaling engages bladder urothelial defenses that limit urinary tract infection [ Cell Rep, 2024, 43(4):114007]	PubMed: 38517889
CK2 activity is crucial for proper glucagon expression [ Diabetologia, 2024, 10.1007/s00125-024-06128-1]	PubMed: 38503901
Modeling unveils sex differences of signaling networks in mouse embryonic stem cells [ Mol Syst Biol, 2023, e11510.]	PubMed: 37735975
Targeting the E3 ligase NEDD4 as a novel therapeutic strategy for IGF1 signal pathway-driven gastric cancer [ Oncogene, 2023, 42(14):1072-1087]	PubMed: 36774408
Targeting the E3 ligase NEDD4 as a novel therapeutic strategy for IGF1 signal pathway-driven gastric cancer [ Oncogene, 2023, 42(14):1072-1087]	PubMed: 36774408
RAGE inhibition blunts insulin-induced oncogenic signals in breast cancer [ Breast Cancer Res, 2023, 25(1):84]	PubMed: 37461077
Young and undamaged recombinant albumin alleviates T2DM by improving hepatic glycolysis through EGFR and protecting islet β cells in mice [ J Transl Med, 2023, 21(1):89]	PubMed: 36747238
EHD1-dependent traffic of IGF-1 receptor to the cell surface is essential for Ewing sarcoma tumorigenesis and metastasis [ Commun Biol, 2023, 6(1):758]	PubMed: 37474760

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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