| CAS |
No.2200214-93-1 |
| 英文名称 |
SHP099 HCl |
| 分子式 |
C16H20Cl3N5 |
| 分子量 |
388.72 |
| 溶解性 |
Soluble in Water/DMSO ≥0.1mg/mL(Need ultrasonic or Water bath) |
| 纯度 |
≥98% |
| 外观(性状) |
Solid |
| 储存条件 |
Powder: 2-8℃，2 years |
| SMILES |
CC1(CCN(CC1)C2=CN=C(C(=N2)N)C3=C(C(=CC=C3)Cl)Cl)N.Cl |
| InChIKey |
KHQHYRFUYAXWOQ-UHFFFAOYSA-N |
| InChI |
InChI=1S/C16H19Cl2N5.ClH/c1-16(20)5-7-23(8-6-16)12-9-21-14(15(19)22-12)10-3-2-4-11(17)13(10)18;/h2-4，9H，5-8，20H2，1H3，(H2，19，22);1H |
| PubChem CID |
121241170 |
| 靶点 |
SHP2 |
| 通路 |
Metabolic Enzyme&Protease |
| 背景说明 |
是有效的，选择性的SHP2 抑制剂。 |
| 生物活性 |
SHP099 hydrochloride is a potent， selective and orally available SHP2 inhibitor with an IC50 of 70 nM.[1-3] |
| IC50 |
IC50: 70 nM (SHP2)[1] |
| In Vitro |
The X-ray co-crystal for SHP099 with SHP2 reveals a new interaction with the basic amine and the Phe113 backbone carbonyl. SHP099 shows inhibition of cell proliferation (KYSE-520 model) with an IC50 of 1.4 μM. SHP099 shows high solubility and high permeability with no apparent efflux in Caco-2 cells[1]. SHP099 concurrently binds to the interface of the N-terminal SH2， C-terminal SH2， and protein tyrosine phosphatase domains， thus inhibiting SHP2 activity through an allosteric mechanism. SHP099 suppresses RAS–ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells[2]. |
| In Vivo |
After a single doses of 30 and 100 mg/kg ， dose-dependent exposure and modulation of the pharmacodynamic marker p-ERK is observed in the xenografts. A daily oral dose of 10 or 30 mg/kg yield 19% and 61% tumor growth inhibition， respectively. Tumor stasis is achieved at 100 mg/kg[1]. |
| 细胞实验 |
Cells are plated onto 96-well plates in 100 μL medium. SHP099 with various concentrations (1.25， 2.5， 5， 10， 20 μM) are added 24 h after cell plating. At day 5， 50 μL Celltiter-Glo reagent is added， and the luminescent signal is determined[1]. |
| 激酶实验 |
The inhibition of SHP2 from the tested compounds (SHP099) concentrations varying from 0.003-100 μM is monitored using an assay in which 0.5 nM of SHP2 is incubated with of 0.5 μM of peptide IRS1_pY1172(dPEG8)pY1222. After 30-60 minutes incubation at the surrogate substrate， DiFMUP is added to the reaction and incubated at 25 °C for 30 minutes. The reaction is then quenched by the addition of 5 μL of a 160 μM solution of bpV(Phen). The fluorescence signal is monitored using a microplate reader using excitation and emission wavelengths of 340 nm and 450 nm， respectively[1]. |
| 数据来源文献 |
[1]. Garcia Fortanet J， et al. Allosteric Inhibition of SHP2: Identification of a Potent， Selective， and Orally Efficacious Phosphatase Inhibitor. J Med Chem. 2016 Sep 8;59(17):7773-82.
[2]. Chen YN， et al. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature. 2016 Jul 7;535(7610):148-52.
[3]. Carmine Fedele， et al. SHP2 Inhibition Abrogates MEK inhibitor Resistance in Multiple Cancer Models. bioRxiv. April 25， 2018. |
| 规格 |
1mg 5mg 10mg 50mg |
| 单位 |
瓶 |
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英语
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