Novel MAP Kinase Pathway Inhibitors to Treat Pancreatic Ductal AdenoCarcinoma

DESCRIPTION provided by applicant Patients diagnosed with advanced pancreatic ductal adenocarcinoma PDAC have a year survival rate of less than These tumors have the highest reported incidence of KRAS mutations among all human cancers Because of these observations there has been considerable interest in developing direct inhibitors of RAS mutants such as KRAS However attempts to directly inhibit KRAS have to date been unsuccessful An alternative approach is to target downstream effectors of KRAS on the MAPK pathway Extracellular Regulated Kinase and ERK are serine threonine protein kinases which are downstream components of the RAS RAF MEK signal transduction pathway Aberrant activation of ERK has been demonstrated in many human tumors including pancreatic cancer ERK inhibitors could prove very useful as therapies to treat tumors with RAS mutations such as PDAC This proposal aims to determine the potential of Kalyraandapos s novel ERK inhibitors as treatments for PDAC via the following aims Phase Characterization of Novels Leads in Models of Pancreatic Cancer Aim Evaluate lead molecules in preliminary in vitro ADME and Plasma Protein Binding studies Aim Confirm efficacy of lead molecules vs a panel of human RAS mutant pancreatic cancer cell lines Aim Determine PK and in vivo efficacy of top leads in an in vivo model of KRAS pancreatic cancer Phase II Additional studies to enable selection of a Development Candidate Aim Characterize the effects of lead ERK inhibitors in combination studies Aim ADME and Preliminary Toxicology Aim Pharmcokinetics for Species Selection for Toxicology and Pilot Toxicology PUBLIC HEALTH RELEVANCE Pancreatic ductal adenocarcinoma PDAC is almost universally fatal The annual number of deaths equals the number of newly diagnosed cases despite maximal treatment with current standard of care Kalyra is developing a novel orally bioavailable MAP kinase pathway inhibitor with a new mechanism of action Kalyraandapos s novel inhibitors offer the potential to deliver best in class drugs for inhibiting the MAP Kinase pathway both in terms of efficacy and tolerability These inhibitors offer the potential to effectively tret patients whose cancers are associated with activation of the MAP kinase pathway which include those with PDAC With lead molecules in hand this proposal aims to conduct the non clinical studies required to select a development candidate with the goal of developing a novel safe and well tolerated therapy for the treatment of PDAC