Inhibitors of Perk Kinase

About

Background: The development and persistence of solid and hematologic tumors, including some aspects of their resistance to chemotherapy, are dependent on cellular pathways that help them cope with high levels of organelle stress. These pathways, termed the unfolded protein response (UPR) and the integrated stress response (ISR), help to balance the high demands placed on the endoplasmic reticulum (ER) of cancerous cells. By tuning translational and secretory output, cancer cells are able to live in the extreme hypoxic conditions of the tumor and/or chemotherapeutic environment. A comprehensive understanding of the UPR and ISR and its role normal cell physiology has led to increasing appreciation of its significance in tumor biology. In response to the low oxygen environment of a tumor or the chemical stress induced by chemotherapies, cancerous cells are burdened by an overload of improperly folded protein in the endoplasmic reticulum. In order to cope with this oxidative stress, protein kinases of the UPR signaling cascade communicate with the cell’s translational machinery and suppress normal protein synthesis. A large subclass of pro-cancerous proteins, including those involved in angiogenesis, adhesion, and protein folding, are able to circumvent this suppression. These proteins help drive the cell to survive and thrive under otherwise hostile conditions. Strong correlations between a tumor’s resistance to chemotherapy and upregulation of the UPR signaling pathway underlies the importance of targeting regulators of the stress response in cancer. Upon sensing unfolded protein in the endoplasmic reticulum the regulatory kinase, PERK, triggers a phosphorylation cascade that results in a global repression of protein translation.  The clinical importance of PERK as a target for chemotherapeutic intervention is highlighted by the discovery that Bortezomib, a currently marketed treatment for multiple myeloma, has been shown to perturb the PERK signaling cascade as one of its anti-myeloma effects.  Description: Using a novel drug discovery platform utilizing in silico pharmacophore screening and biochemical assays, Dr. Cardozo has discovered a panel of novel inhibitory compounds, which selectively inhibit PERK kinase activity. These compounds have near-nanomolar IC50’s and display specific activity to PERK when compared to another protein kinase.  Applications: The compounds emerging from these leads can be used to treat multiple myeloma alone or in combination with existing chemotherapy or radiation treatments. PERK inhibitors might be used to treat solid tumors that have increased UPR signaling such as lung, breast, liver, gastric, and colon cancer.