Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity

Area of Science:

• Molecular Biology
• Cellular Stress Response
• Cancer Therapeutics

Background:

• The unfolded protein response (UPR) is crucial for cellular adaptation to stress, with its components being attractive therapeutic targets in oncology.
• Tumor microenvironments frequently exhibit stress conditions like hypoxia and nutrient deprivation, activating the UPR.

Purpose of the Study:

• To identify and characterize a novel small molecule inhibitor of eukaryotic initiation factor 2-alpha kinase 3 (EIF2AK3), also known as PERK.
• To evaluate the in vitro and in vivo efficacy and safety of the PERK inhibitor GSK2656157 as a potential cancer therapeutic.

Main Methods:

• GSK2656157 was assessed for its inhibitory activity against PERK enzyme and a panel of kinases.
• In vitro studies evaluated GSK2656157's effect on PERK signaling pathways (autophosphorylation, eIF2α phosphorylation, ATF4, CHOP) in cancer cell lines.
• In vivo studies involved oral administration to mice bearing human tumor xenografts to assess pharmacodynamics and antitumor efficacy.

Main Results:

• GSK2656157 is a potent and selective ATP-competitive inhibitor of PERK (IC50 = 0.9 nmol/L).
• The compound effectively inhibited PERK signaling in multiple cell lines and demonstrated dose-dependent pharmacodynamic effects in mouse pancreas.
• GSK2656157 significantly inhibited the growth of human tumor xenografts in mice, with potential mechanisms including altered amino acid metabolism and reduced angiogenesis.

Conclusions:

• GSK2656157 represents a first-in-class PERK inhibitor with demonstrated preclinical antitumor activity.
• Further clinical development of PERK inhibitors requires careful consideration of on-target effects on pancreatic function.