SHP099 HCl

Catalog No.S8278 Batch:S827806

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Technical Data

Formula

C16H20Cl3N5
Molecular Weight 388.72 CAS No. 2200214-93-1
Solubility (25°C)* In vitro DMSO 78 mg/mL (200.65 mM)
Water 6 mg/mL (15.43 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.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description 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.
Targets
SHP-2 [1]
(Cell-free assay)
0.07 μM
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].

Protocol (from reference)

Cell Assay:

[1]
  • Cell lines

    KYSE-520 cells

  • Concentrations

    20, 6.6, 2.2, 0.74, 0.24, 0.08, and 0.027 μM

  • Incubation Time

    2 h

  • 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.
Animal Study:

[1]
  • Animal Models

    Nude mice (Tumor Xenograft)

  • Dosages

    10, 30, or 100 mg/kg qd

  • Administration

    by oral gavage

Selleck's SHP099 HCl has been cited by 53 publications

LILRB1-HLA-G axis defines a checkpoint driving natural killer cell exhaustion in tuberculosis [ EMBO Mol Med, 2024, 10.1038/s44321-024-00106-1] PubMed: 39030302
Allosteric inhibitor of SHP2 enhances macrophage endocytosis and bacteria elimination by increasing caveolae activation and protects against bacterial sepsis [ Pharmacol Res, 2024, 201:107096] PubMed: 38320736
Pharmacological inhibition of the Src homology phosphatase 2 confers partial protection in a mouse model of alcohol-associated liver disease [ Biomed Pharmacother, 2024, 175:116590] PubMed: 38653109
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

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

NOT FOR HUMAN, VETERINARY DIAGNOSTIC OR THERAPEUTIC USE.