Malic Enzyme 1 Inhibitors for Pancreatic and Gastrointestinal Cancers

Background & Unmet Need

• Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive cancer with a 5-year survival rate of only 10% and no effective therapies
• PDAC, among other cancer types, frequently exhibits loss of tumor suppressor SMAD4, which is often associated with co-deletion of the nearby housekeeping enzyme, malic enzyme 2 (ME2)
• This SMAD4/ME2 co-deletion is observed in ~20% of PDAC and >6% of gastrointestinal cancers
• Malic Enzyme 1 (ME1) and ME2 belong to the same family of enzymes, which are involved in several essential metabolic processes and are likely to be functionally redundant
• Deletion of ME1 in ME2-mull tumors may confer synthetic lethality, making it a good target for selective killing of ME2-null pancreatic cancers
• Unmet Need: Inhibitors of ME1 for treatment of PDAC and other ME2-null cancers

Technology Overview

• The Technology: A small-molecule inhibitor of ME1, AS1134900, for treatment of PDAC and gastrointestinal cancers
• AS1134900 was identified from a proprietary chemical library (Astellas Pharma) through a diaphorase/resazurin-coupled assay for measuring ME1 enzymatic activity
• AS1134900 inhibits ME1 activity by allosteric binding and doesn’t have cross reactivity for ME2
• PoC Data: Validated inhibition of ME1 activity (IC50 = 0.73μM)
• ME1 inhibition in ME2-null pancreatic cancer cells and xenograft tumors leads to profound growth inhibition
• ME1 knockout in adult mice leads to enhanced CD8+ T cells and their infiltrations to tumors, suggesting potential synergy with immunotherapy

Technology Applications

• Treatment of patients with ME2-null PDAC
• Treatment of patients with other ME2-null gastrointestinal cancers, such as colon, esophagus, biliary, and stomach cancer

Technology Advantages

• Inhibitor is specific for ME1 and does not have cross reactivity for ME2
• Potential synergy for ME1 inhibitors in combination of with checkpoint blockade therapy
• ME2 expression may be a biomarker for patient selection in ME1 inhibitor therapy
• Off-target toxicity of ME1 deletion was not observed in genetic models

Figure 1: Top: Structure of ME1 inhibitor and Diaphorase/resazurincoupled ME1 assay used to identify the inhibitor Bottom: Inhibition of ME1 and ME2 activities by AS1134900.