Abstract 4542: Towards the identification of PKR-like endoplasmic reticulum kinase (PERK) inhibitors.

Abstract

Abstract During tumorgenesis cancer cells must tolerate cellular stresses such as DNA damage, hypoxia, and oxidative stress. In order to adapt to and overcome such stresses, tumor cells remodel transcriptional and translational programs by activating pro-survival signaling pathways. PERK (PKR-like endoplasmic reticulum kinase) is one of the key components of the unfolded protein response (UPR). Many studies report that the UPR is activated in a variety of tumor types. Previous studies demonstrated that cells with a compromised PERK-eIF2α-ATF4 signaling pathway are sensitive to hypoxic stress in vitro and form tumors that grow more slowly in vivo. Together, these data suggest a substantial role for PERK and the UPR in tumor cell survival and adaptation to stress. Thus, selective inhibitors of PERK activity may be useful therapeutic candidates for the treatment of cancer. Using a high-throughput screening (HTS) approach a number of lead compounds were identified with demonstrated ability to inhibit PERK kinase autophosphorylation and activity in cells. Using a publically available structure of Apo PERK a PERK-ATP complex structure was generated by means of molecular dynamics (MD) simulation. Evidence is presented to support the notion that the simulation-generated structure represents a useful model for computer-aided lead optimization. Citation Format: Jihyun Park, Qiantao Wang, Pengyu Ren, Kevin N. Dalby. Towards the identification of PKR-like endoplasmic reticulum kinase (PERK) inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4542. doi:10.1158/1538-7445.AM2013-4542