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Malic Enzyme 1 (ME1) Inhibitors for Pancreatic and Gastrointestinal Cancers
Weill Cornell Medicine
Small molecule
Oncology
Hit To Lead or Lead Optimization
Background
• 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 Needs
Inhibitors of ME1 for treatment of PDAC and other ME2-null cancers
Technology Overview
• 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
• AS1134900 inhibits ME1 activity by allosteric binding and doesn’t have cross reactivity for ME2
• ME1 knockout in adult mice leads to enhanced CD8+ T cells and their infiltrations to tumors, suggesting potential synergy with immunotherapy
Lewis C. Cantley
PCT/US2023/062139 (2023.02.07)
Patent Family: PCT
"Discovery and Characterization of a Novel Allosteric Small-Molecule Inhibitor of NADP+-Dependent Malic Enzyme 1". Yoshida, T. et al. Biochemistry, 61(15), 1548–1553
