SHP099 HCl

Catalog No.S8278

SHP099 HCl Chemical Structure

Molecular Weight(MW): 388.72

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.

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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].

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
MGH049-1A NWn6c2RCTnWwY4Tpc44h[XO|YYm= NHPEXlc2KM7:TR?= MY[xOEBl[Xm| NF7iPGJCeyCjIIPpcodt\SCjZ3XueEwhW0iSMEm5JIhi\CCvaX7pcYFtKGWoZnXjeEBwdiClZXzsJJBzd2yrZnXyZZRqd25? NGXqWW8zQTVyNUCzNy=>
MGH073-2B NFPtcllHfW6ldHnvckBie3OjeR?= MYq1JO69VQ>? NYTsem5ROTRiZHH5dy=> MmHXRZMh[SC|aX7ncIUh[WenboSsJHNJWDB7OTDoZYQhdWmwaX3hcEBm\m[nY4Sgc44h[2WubDDwdo9tcW[ncnH0bY9v MYeyPVUxPTB|Mx?=
MGH065-1B M3u0dGZ2dmO2aX;uJIF{e2G7 MX[1JO69VQ>? M2eyUFE1KGSjeYO= MmrNRZMh[SC|aX7ncIUh[WenboSsJHNJWDB7OTDoZYQhdWmwaX3hcEBm\m[nY4Sgc44h[2WubDDwdo9tcW[ncnH0bY9v M1PlN|I6PTB3MEOz
MGH045-2A NWfpOIhPTnWwY4Tpc44h[XO|YYm= MUm1JO69VQ>? NV\remJoOTRiZHH5dy=> MYTBd{BiKHOrbnfs[UBi\2WwdDygV2hRODl7IHjh[EBucW6rbXHsJIVn\mWldDDvckBk\WyuIIDyc4xq\mW{YYTpc44> MUGyPVUxPTB|Mx?=
U2OS cells Mo[2SpVv[3Srb36gZZN{[Xl? NH7IUocxNCBzLDCzMEA3NCBzMjygNlUtKDVyIN88US=> NYPme4pTW0iSMEm5JJJm\HWlZYOgdGVzcyCuZY\lcJMhcW5id3ns[E11gXCnIGWyU3Mh[2WubIOu M3fjflMxOzd3M{i4
KYSE-520 M3Lqb3Bzd2yrZnXyZZRqd25iYYPzZZk> MYK1JIRigXN? MXXpcohq[mm2aX;uJI9nKGOnbHygdJJwdGmoZYLheIlwdiC5aYToJIFvKEmFNUCgc4YhOS52IN88US=> NFW2SZMzPzN2N{[5Ni=>

... Click to View More Cell Line Experimental Data

Assay
Methods Test Index PMID
Western blot
pERK / Bcl-xL / p85 PARP; 

PubMed: 29568093     


Immunoblot analysis of cell lysates after 2 days of SHP099 treatment.

pMEK / MEK / pERK / Erk; 

PubMed: 30605687     


The same cell lines were treated with SHP (5 μM), and the pERK rebound was monitored for 24 hr by immunoblotting with the indicated antibodies.

EGFR / pEGFR / GAB1 / pSHP2 / GRB2 / SOS1; 

PubMed: 30605687     


HeLa cells were pretreated with either DMSO or SHP099 (SHP, 10 μM) for 1 hr before stimulation with epidermal growth factor (EGF, 10 ng/mL) for the indicated times. Cell lysates were either subjected to immunoprecipitation with a SHP2 antibody, followed by immunoblotting, or immunoblotted with the indicated antibodies.

29568093 30605687
Growth inhibition assay
Cell viability; 

PubMed: 29568093     


Growth inhibiting activity of SHP099 in the four SHP2 mutant cell lines. Cells were cultured in GM-CSF free medium with indicated concentrations of SHP099 and viable cells were measured on Day 5.

29568093
Immunofluorescence
insulin receptor; 

PubMed: 30931927     


HepG2 cells expressing IR-GFP WT were starved, treated with the indicated inhibitors for 2 h, treated without or with 100 nM insulin for 20 min, and stained with anti-GFP (IR; green) and DAPI (blue). Scale bar, 5 µm.

30931927
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

Cell Research:

[1]

+ Expand
  • 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.


    (Only for Reference)
Animal Research:

[1]

+ Expand
  • Animal Models: Nude mice (Tumor Xenograft)
  • Formulation: --
  • Dosages: 10, 30, or 100 mg/kg qd
  • Administration: by oral gavage
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 77 mg/mL warmed (198.08 mM)
Water 2 mg/mL warmed (5.14 mM)
Ethanol Insoluble
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
2% DMSO+ddH2O
For best results, use promptly after mixing.
5mg/mL

* 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.

Chemical Information

Molecular Weight 388.72
Formula

C16H20Cl3N5

CAS No. 1801747-42-1(free base)
Storage powder
in solvent
Synonyms N/A

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Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID