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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. 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.
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.
Cell Rep. 2022 Jul 26;40(4):111095.
High-risk neuroblastoma with NF1 loss of function is targetable using SHP2 inhibition
SHP099 purchased from AbMole
Cancer Res Commun. 2022 Aug.
Pharmacological inhibition of SHP2 blocks both PI3K and MEK signaling in low-epiregulin HNSCC via GAB1
SHP099 purchased from AbMole
| Cell Experiment | |
|---|---|
| Cell lines | KYSE-520 cells |
| Preparation method | 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. |
| Concentrations | 20, 6.6, 2.2, 0.74, 0.24, 0.08, and 0.027 μM |
| Incubation time | 2 h |
| Animal Experiment | |
|---|---|
| Animal models | Nude mice (Tumor Xenograft) |
| Formulation | |
| Dosages | 10, 30, or 100 mg/kg qd |
| Administration | oral gavage |
| Molecular Weight | 352.26 |
| Formula | C16H19Cl2N5 |
| CAS Number | 1801747-42-1 |
| Solubility (25°C) | DMSO: ≥ 8 mg/mL (Need ultrasonic and warming) |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Related Phosphatase Products |
|---|
| RMC-3943
RMC-3943 is an allosteric SHP2 inhibitor (inhibition of full-length SHP2 in biochemical assay, IC50 = 2.19 nM). |
| LYP-IN-1
LYP-IN-1 is a potent, selective and specific LYP inhibitor with a Ki and an IC50 of 110 nM and 0.259 μM, respectively. |
| PF-07284892
PF-07284892 (ARRY-558) is a potent and orally active SHP2 inhibitor with an IC50 value of 21 nM. |
| MY10
MY10 is a potent and orally active receptor protein tyrosine phosphatase (RPTPβ/ζ) inhibitor. |
| CPDA
CPDA is a novel potent SH2 domain-containing inositol phosphatase 2 (SHIP2) inhibitor. |
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