Kinase Drug Discovery: The Road Less Traveled, Translational Oncology Seminar Series

Amar Natarajan, Ph.D.
Professor
Eppley Institute for Cancer Research
Fred and Pamela Buffett Cancer Center
University of Nebraska Medical Center

Refreshments will be provided.

ABSTRACT: Mutations in Kras are associated with ~30% of all cancer patients and ~90% of pancreatic ductal adenocarcinoma (PDAC) patients. Pancreas specific expression of KrasG12D mutant leads to PDAC in ~20% of mice, however none of the mice developed PDAC when IKKß was concurrently inactivated in the above model. This implicates IKKß as a potential target for therapeutic intervention for Kras mutation driven cancers. Several small molecule IKKß inhibitors were developed by pharmaceutical industry to treat chronic inflammatory diseases. Nearly all IKKß inhibitors developed were ATP-competitive. Despite complete preclinical characterization of many candidates, to date FDA has approved none of them for clinical use. This is because ATP competitive IKKß inhibitors exhibited on target off site activity associated toxicity in animals. Through unbiased screens and iterative SAR studies we discovered a non-ATP competitive IKKß inhibitor that does not share the toxicity profile observed with ATP competitive IKKß inhibitors. Moreover in an orthotopic pancreatic tumor model, mice treated with our inhibitor showed reduced tumor growth and metastasis compared to vehicle controls. The median survival of mice treated with our inhibitor nearly doubled when compared vehicle treated mice in a mantle cell lymphoma model. Follow up hit-to-lead optimizations have led to pre-therapeutic lead compound with improved potency, ADME properties and in vivo anti-tumor efficacy. The lecture will cover the path starting from unbiased screens to the development of a pre-therapeutic anti-cancer agent.