GSK-2256098
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MedKoo CAT#: 205482

CAS#: 1224887-10-8 (free base)

Description: GSK2256098, also known as GTPL7939, is a focal adhesion kinase-1 (FAK) inhibitor with potential antiangiogenic and antineoplastic activities. FAK inhibitor GSK2256098 inhibits FAK, which may prevent the integrin-mediated activation of several downstream signal transduction pathways, including ERK, JNK/MAPK and PI3K/Akt, thereby inhibiting tumor cell migration, proliferation and survival, and tumor angiogenesis. The tyrosine kinase FAK is normally activated by binding to integrins in the extracellular matrix (ECM) but may be upregulated and constitutively activated in various tumor cell types.


Chemical Structure

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GSK-2256098
CAS# 1224887-10-8 (free base)

Theoretical Analysis

MedKoo Cat#: 205482
Name: GSK-2256098
CAS#: 1224887-10-8 (free base)
Chemical Formula: C20H23ClN6O2
Exact Mass: 414.1571
Molecular Weight: 414.894
Elemental Analysis: C, 57.90; H, 5.59; Cl, 8.54; N, 20.26; O, 7.71

Price and Availability

Size Price Availability Quantity
10.0mg USD 120.0 Ready to ship
25.0mg USD 250.0 Ready to ship
50.0mg USD 450.0 Ready to ship
100.0mg USD 750.0 Ready to ship
200.0mg USD 1250.0 Ready to ship
500.0mg USD 2150.0 Ready to ship
1.0g USD 3250.0 Ready to ship
2.0g USD 5450.0 2 weeks
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Related CAS #: 1416771-10-2 (HCl)   1224887-10-8 (free base)    

Synonym: GSK2256098; GSK 2256098; GSK-2256098; GTPL7939; GTPL-7939; GTP L7939.

IUPAC/Chemical Name: 2-((5-chloro-2-((1-isopropyl-3-methyl-1H-pyrazol-5-yl)amino)pyridin-4-yl)amino)-N-methoxybenzamide

InChi Key: BVAHPPKGOOJSPU-UHFFFAOYSA-N

InChi Code: InChI=1S/C20H23ClN6O2/c1-12(2)27-19(9-13(3)25-27)24-18-10-17(15(21)11-22-18)23-16-8-6-5-7-14(16)20(28)26-29-4/h5-12H,1-4H3,(H,26,28)(H2,22,23,24)

SMILES Code: CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NOC)Cl)C(C)C

Appearance: White to off-white solid powder.

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: FAK kinase inhibitor with Ki of 0.4 nM.
In vitro activity: Focal adhesion kinase (FAK) hyperactivation is common in pancreatic ductal adenocarcinoma (PDAC). GSK2256098 inhibits FAK activity through targeting the phosphorylation site of FAK, tyrosine (Y) 397. In order to determine whether GSK2256098 inhibition of FAK Y397 phosphorylation attenuates PDAC-associated cell proliferation, motility and survival, cultured PDAC cells were used as cellular models of GSK2256098-impaired abnormal growth. Western blot analysis, cell viability analysis, clonogenic survival, soft-agar and wound healing assays were performed. GSK2256098 inhibition of FAK Y397 phosphorylation correlated with decreased levels of phosphorylated Akt and ERK in L3.6P1 cells. GSK2256098 decreased cell viability, anchorage-independent growth, and motility in a dose dependent manner. Reference: Cell Cycle. 2014;13(19):3143-9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4615113/
In vivo activity: To examine the effect of GSK2256098 in pre-clinical models of uterine cancer, orthotopic mouse models of uterine cancer were used. Mice were inoculated with Ishikawa or Hec1a cells. In the Ishikawa model, tumor growth was inhibited to a greater extent in the GSK2256098 monotherapy group (Fig. 3A) as compared to the Hec1A model (Fig. 3B). Extent of distant metastases was also substantially reduced with GSK2256098-based therapy. All tumor models in mice treated with GSK2256098 exhibited less proliferation via Ki67 than control. Ishikawa tumors had the lowest Ki67 expression in response to therapy. Ishikawa tumors had higher apoptotic indices than Hec1A tumors after treatment with GSK2256098. Reference: Mol Cancer Ther. 2015 Jun;14(6):1466-1475. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4458384/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 47.33 114.08
DMF 30.0 72.31
Ethanol 56.0 134.98
Ethanol:PBS (pH 7.2) (1:4) 0.2 0.48

Preparing Stock Solutions

The following data is based on the product molecular weight 414.894 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Zhang J, He DH, Zajac-Kaye M, Hochwald SN. A small molecule FAK kinase inhibitor, GSK2256098, inhibits growth and survival of pancreatic ductal adenocarcinoma cells. Cell Cycle. 2014;13(19):3143-9. doi: 10.4161/15384101.2014.949550. PMID: 25486573; PMCID: PMC4615113. 2. Thanapprapasr D, Previs RA, Hu W, Ivan C, Armaiz-Pena GN, Dorniak PL, Hansen JM, Rupaimoole R, Huang J, Dalton HJ, Ali-Fehmi R, Coleman RL, Sood AK. PTEN Expression as a Predictor of Response to Focal Adhesion Kinase Inhibition in Uterine Cancer. Mol Cancer Ther. 2015 Jun;14(6):1466-1475. doi: 10.1158/1535-7163.MCT-14-1077. Epub 2015 Apr 1. PMID: 25833835; PMCID: PMC4458384.
In vitro protocol: 1. Zhang J, He DH, Zajac-Kaye M, Hochwald SN. A small molecule FAK kinase inhibitor, GSK2256098, inhibits growth and survival of pancreatic ductal adenocarcinoma cells. Cell Cycle. 2014;13(19):3143-9. doi: 10.4161/15384101.2014.949550. PMID: 25486573; PMCID: PMC4615113.
In vivo protocol: 1. Thanapprapasr D, Previs RA, Hu W, Ivan C, Armaiz-Pena GN, Dorniak PL, Hansen JM, Rupaimoole R, Huang J, Dalton HJ, Ali-Fehmi R, Coleman RL, Sood AK. PTEN Expression as a Predictor of Response to Focal Adhesion Kinase Inhibition in Uterine Cancer. Mol Cancer Ther. 2015 Jun;14(6):1466-1475. doi: 10.1158/1535-7163.MCT-14-1077. Epub 2015 Apr 1. PMID: 25833835; PMCID: PMC4458384.

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 1: Thanapprapasr D, Previs RA, Hu W, Ivan C, Armaiz-Pena GN, Dorniak PL, Hansen JM, Rupaimoole R, Huang J, Dalton HJ, Ali-Fehmi R, Coleman RL, Sood AK. PTEN Expression as a Predictor of Response to Focal Adhesion Kinase Inhibition in Uterine Cancer. Mol Cancer Ther. 2015 Jun;14(6):1466-75. doi: 10.1158/1535-7163.MCT-14-1077. Epub 2015 Apr 1. PubMed PMID: 25833835; PubMed Central PMCID: PMC4458384.

2: Zhang J, He DH, Zajac-Kaye M, Hochwald SN. A small molecule FAK kinase inhibitor, GSK2256098, inhibits growth and survival of pancreatic ductal adenocarcinoma cells. Cell Cycle. 2014;13(19):3143-9. doi:
10.4161/15384101.2014.949550. PubMed PMID: 25486573; PubMed Central PMCID: PMC4615113.

3: Schultze A, Fiedler W. Clinical importance and potential use of small molecule inhibitors of focal adhesion kinase. Anticancer Agents Med Chem. 2011 Sep;11(7):593-9. Review. PubMed PMID: 21787277.



Additional Information

Interim Clinical trial results with GSK2256098 : 57 pts with advanced solid tumors have been treated at escalating doses ranging from 80 mg to 1500 mg BID: median age=58.8 (range 21-84). The most common tumor types include: mesothelioma (23), ovary (7), colon (3), kidney (3), and pancreas (3). MTD was determined to be 1000 mg BID. DLTs were Gr 2 proteinuria (1000 mg), Gr 2 nausea, vomiting, fatigue (1250 mg) and Gr 3 asthenia (1500 mg). Most frequent toxicities were nausea (32 pts, 56%), diarrhea (31 pts, 54%), vomiting (25 pts, 44%), decreased appetite (18 pts 32%) and asthenia (11 pts, 19%). The majority of toxicities were Gr 1-2; Gr 3 drug-related events included hypertriglyceridemia (n=2), hyperlipasemia (2), asthenia (1), increased amylase (1), and loss of consciousness (1). Few dose reductions and interruptions have occurred. Minor responses/stable disease (SD) were observed in pts with mesothelioma (-12%, 27 wks), melanoma (-26%, 54 wks), and naso/pharyngeal cancer (-31% target lesion, 30 wks) and SD in renal cell (48+ wks). In preliminary analysis of single-dose PK, exposure generally increased in a dose-proportional manner, and the geometric mean tÅ“ was 4.2 h. Accumulation was not observed with repeat dosing. Conclusions: GSK2256098 is well tolerated with evidence of clinical activity. PK supports BID dosing.  (source: J Clin Oncol 30, 2012 (suppl; abstr 3000)