GSK2656157 - CAS 1337532-29-2
Catalog number:
1337532-29-2
Category:
Inhibitor
Not Intended for Therapeutic Use. For research use only.
COA:
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Targets:
PERK
Description:
GSK2656157 is an ATP-competitive inhibitor of PERK enzyme activity with an IC50 of 0.9 nM. It is highly selective for PERK with IC50 values >100 nM against a panel of 300 kinases. GSK2656157 inhibits PERK activity in cells with an IC50 in the range of 10-30 nM as shown by inhibition of stress-induced PERK autophosphorylation, eIF2α substrate phosphorylation, together with corresponding decreases in ATF4 and CHOP proteins in multiple cell lines. Oral administration of GSK2656157 to mice shows a dose- and time-dependent pharmacodynamic response in pancreas as measured by PERK auto-phosphorylation. Twice daily dosing of GSK2656157 results in dose dependent inhibition of multiple human tumor xenografts growth in mice. Altered amino acid metabolism, decreased blood vessel density and vascular perfusion are potential mechanisms for the observed anti-tumor effect. However, despite its anti-tumor activity, given the on-target pharmacological effects of PERK inhibition on pancreatic function, development of any PERK inhibitor in human subjects would need to be cautiously pursued in cancer patients.
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Purity:
0.98
Appearance:
white to light yellow solid powder
Synonyms:
GSK2656157; GSK 2656157; GSK-2656157.
MSDS:
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Current Developer:
GSK
1.Evidence for eIF2α phosphorylation-independent effects of GSK2656157, a novel catalytic inhibitor of PERK with clinical implications.
Krishnamoorthy J1, Rajesh K1, Mirzajani F1, Kesoglidou P1, Papadakis AI1, Koromilas AE2. Cell Cycle. 2014;13(5):801-6. doi: 10.4161/cc.27726. Epub 2014 Jan 8.
The endoplasmic reticulum (ER)-resident protein kinase PERK is a major component of the unfolded protein response (UPR), which promotes the adaptation of cells to various forms of stress. PERK phosphorylates the α subunit of the translation initiation factor eIF2 at serine 51, a modification that plays a key role in the regulation of mRNA translation in stressed cells. Several studies have demonstrated that the PERK-eIF2α phosphorylation pathway maintains insulin biosynthesis and glucose homeostasis, facilitates tumor formation and decreases the efficacy of tumor treatment with chemotherapeutic drugs. Recently, a selective catalytic PERK inhibitor termed GSK2656157 has been developed with anti-tumor properties in mice. Herein, we provide evidence that inhibition of PERK activity by GSK2656157 does not always correlate with inhibition of eIF2α phosphorylation. Also, GSK2656157 does not always mimic the biological effects of the genetic inactivation of PERK.
2.Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development.
Axten JM1, Romeril SP1, Shu A1, Ralph J1, Medina JR1, Feng Y1, Li WH1, Grant SW1, Heerding DA1, Minthorn E1, Mencken T1, Gaul N2, Goetz A3, Stanley T3, Hassell AM4, Gampe RT4, Atkins C1, Kumar R1. ACS Med Chem Lett. 2013 Aug 12;4(10):964-8. doi: 10.1021/ml400228e. eCollection 2013.
We recently reported the discovery of GSK2606414 (1), a selective first in class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), which inhibited PERK activation in cells and demonstrated tumor growth inhibition in a human tumor xenograft in mice. In continuation of our drug discovery program, we applied a strategy to decrease inhibitor lipophilicity as a means to improve physical properties and pharmacokinetics. This report describes our medicinal chemistry optimization culminating in the discovery of the PERK inhibitor GSK2656157 (6), which was selected for advancement to preclinical development.
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