SHP099 HCl

製品コードS8278 バッチS827805

印刷

化学情報

Chemical Structure Synonyms N/A Storage
(From the date of receipt)		 3 years -20°C powder
1 years -80°C in solvent
化学式

C16H20Cl3N5
分子量 388.72 CAS No. 2200214-93-1
Solubility (25°C)* 体外 DMSO 10 mg/mL warmed with 50ºC water bath (25.72 mM)
Water 10 mg/mL warmed with 50ºC water bath (25.72 mM)
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 SHP099 is a highly potent, selective and orally bioavailable small-molecule SHP2 inhibitor with an IC50 value of 0.071 μM and shows no activity against SHP1.
in vitro SHP099 shows inhibition of cell proliferation (KYSE-520 model) with an IC50 of 1.4 μM. In both phosphatase and kinase panels, no biochemical inhibitory activity is evident, suggesting that the aminopyrazine series(SHP099) is quite selective for SHP2. Moreover, SHP099 shows high solubility (>0.5 mM in pH 6.8 buffer) and high permeability with no apparent efflux in Caco-2 cells[1]. SHP099 stabilizes SHP2 in an auto-inhibited conformation. SHP099 suppresses RAS-ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro. SHP099 only has modest activity against 5HT3 when profiled against a preclinical safety pharmacology panel representing 49 common adverse drug reaction targets. SHP099 shows no activity against SHP1, the closest homologue of SHP2 sharing 61% amino acid sequence identity, supporting its high degree of target selectivity. It inhibits p-ERK with an IC50 of ~0.25 μM in SHP2-dependent MDA-MB-468 and KYSE520 cells, but not in A2058 cells. No effect is observed on p-AKT levels across the same cells. SHP099 inhibits MAPK signalling and proliferation in RTK-dependent cells through direct on-target inhibition of SHP2[2].
in vivo SHP099 shows acceptable oral exposure (5 mg/kg PO, 565 μM/h) and bioavailability (46% F). SHP099 is a potent, selective, highly soluble, orally bioavailable, and efficacious SHP2 inhibitor exhibiting dose-dependent pathway inhibition and antitumor activity in xenograft models[1]. Orally administered SHP099 shows dose-dependent anti-tumour activity in the KYSE520 xenograft model and is well tolerated[2].

プロトコル(参考用のみ)

細胞アッセイ 細胞株 KYSE-520 cells
濃度 20, 6.6, 2.2, 0.74, 0.24, 0.08, and 0.027 μM
反応時間 2 h
実験の流れ

KYSE-520 cells (30,000 cells/well) are grown in 96-well plate culture overnight and treated with SHP2 inhibitors at concentrations of 20, 6.6, 2.2, 0.74, 0.24, 0.08, and 0.027 μM for 2 h at 37 °C. Incubations are terminated by addition of 30 μL of lysis buffer supplied with the SureFire p-ERK assay kit.
動物実験 動物モデル Nude mice (Tumor Xenograft)
投薬量 10, 30, or 100 mg/kg qd
投与方法 by oral gavage

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：

Rational combination of SHP2 and mTOR inhibition for the treatment of hepatocellular carcinoma [ Mol Oncol, 2023, none] PubMed: 36650715
The Immunosuppressive Roles of PD-L1 during Influenza A Virus Infection [ Int J Mol Sci, 2023, 24(10)8586] PubMed: 37239931
The Immunosuppressive Roles of PD-L1 during Influenza A Virus Infection [ Int J Mol Sci, 2023, 24(10)8586] PubMed: 37239931
Identification of therapeutic sensitivities in a spheroid drug combination screen of Neurofibromatosis Type I associated High Grade Gliomas [ PLoS One, 2023, 18(2):e0277324] PubMed: 36730269
Airway epithelial ITGB4 deficiency induces airway remodeling in a mouse model [ J Allergy Clin Immunol, 2022, S0091-6749(22)01342-2] PubMed: 36243221
Phosphorylation of SHP2 at Tyr62 Enables Acquired Resistance to SHP2 Allosteric Inhibitors in FLT3-ITD-Driven AML [ Cancer Res, 2022, 82(11):2141-2155] PubMed: 35311954
Thymosin α-1 Reverses M2 Polarization of Tumor-Associated Macrophages during Efferocytosis [ Cancer Res, 2022, 82(10):1991-2002] PubMed: 35364609
SHP2 inhibition enhances Yes-associated protein-mediated liver regeneration in murine partial hepatectomy models [ JCI Insight, 2022, 7(15)e159930] PubMed: 35763355
Targeting SHP2 phosphatase in breast cancer overcomes RTK-mediated resistance to PI3K inhibitors [ Breast Cancer Res, 2022, 24(1):23] PubMed: 35365185
EMT, Stemness, and Drug Resistance in Biological Context: A 3D Tumor Tissue/In Silico Platform for Analysis of Combinatorial Treatment in NSCLC with Aggressive KRAS-Biomarker Signatures [ Cancers (Basel), 2022, 14(9)2176] PubMed: 35565305

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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