Hasan Alsaid1, Charity Atkins2, Sarah Lee3, Tinamarie Skedzielewski1, Mary V. Rambo1, Shu-Yun Zhang2, David J. Figueroa2, Brandon Whitcher3, Rakesh Kumar2, Beat M. Jucker1
1Preclinical & Translational Imaging, LAS, PTS, GlaxoSmithKline, King of Prussia, PA, United States; 2Oncology R&D, GlaxoSmithKline, Collegeville, PA, United States; 3Mango Solutions, London, United Kingdom
The eukaryotic initiation factor 2-alpha kinase 3 (EIF2AK3) or PERK is one of three mediators of the unfolded protein response signal transduction pathway. GSK2656157 is the first-in-class, small molecule inhibitor of PERK enzyme activity in cells with an IC50 in the range of 10-30 nM as reflected by inhibition of stress-induced PERK autophosphorylation. In this study, we investigated the pharmacological effect of GSK2656157 on tumor growth and angiogenesis using dynamic contrast enhanced MRI (DCE-MRI) in the BxPc3 xenograft tumor model. The results suggest DCE-MRI can be used as a PD marker to monitor the antiangiogenic effect of a PERK inhibition in human subjects.