Potassium-3-beta-hydroxy-20-oxopregn-5-en-17-alpha-yl sulfate: a novel inhibitor of 78 kDa glucose-regulated protein
Received 29 September 2015
Accepted for publication 14 December 2015
Published 3 February 2016 Volume 2016:9 Pages 627—634
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Ram Prasad
Peer reviewer comments 4
Editor who approved publication: Dr Faris Farassati
Nizar M Mhaidat,1,2 Qosay A Al-Balas,1 Karem H Alzoubi,1 Rowan F AlEjielat2
1Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, 2Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Hashemite University, Zarqa, Jordan
Background: Previous studies have shown the central role of 78 kDa glucose-regulated protein (GRP78) in colorectal cancer (CRC) survival and chemoresistance. In the present study, we aimed to design a GRP78 inhibitor and test its potential to inhibit CRC cells growth.
Materials and methods: Computer-aided drug design was used to establish novel compounds as potential inhibitors of GRP78. Discovery Studio 3.5 software was used to evaluate a series of designed compounds and assess their mode of binding to the active site of the protein. The cytotoxicity of the designed compounds was evaluated using the MTT assay and the propidium iodide method. The effect of the inhibitor on the expression of GRP78 was evaluated by immunoblotting.
Results: Among the designed compounds, only potassium-3-beta-hydroxy-20-oxopregn-5-en-17-alpha-yl sulfate (PHOS) has a potential to inhibit the growth of CRC cells. Inhibition of cellular growth was largely attributed to downregulation of GRP78 and induction of apoptotic cell death.
Conclusion: These results introduce PHOS as a promising GRP78 inhibitor that could be used in future studies as a combination with chemotherapy in the treatment of CRC patients. Our ongoing studies aim to characterize PHOS safety profile as well as its mechanism of action.
Keywords: UPR, apoptosis, GRP78, CRC, chemotherapy, computer-aided drug design (CADD)
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