Abstract
Mutations in the Isocitrate Dehydrogenase 2 (IDH2) enzyme have been linked to acute myeloid leukemia (AML). IDH2, involved in the citric acid cycle, normally converts isocitrate to α-ketoglutarate (α-KG), using NADP+ to produce NADPH. Mutations like R140Q and R172K lead IDH2 to convert αKG into the oncometabolite 2-hydroxyglutarate (2HG), hindering blood cell differentiation and resulting in AML.
The drug AG-221 targets mutant IDH2 at an allosteric site, stabilizing the enzyme in an inactive form and preventing 2HG formation, thus alleviating AML symptoms. Most patients, however, require additional chemotherapy and often complete bone marrow transplants. A 3-D printed model based on PDB-IDs: 5I96 and 5I95 illustrates how AG-221, NADPH, and α-KG interact with the mutant IDH2 enzyme. Specific amino acids at the binding interface, including Y311, D312, Q316, L320, I319, L298, L160, and W164, are highlighted to show their interaction with AG-221.
Additionally, the model emphasizes the R140Q mutation, where the relatively larger and positively charged arginine is replaced by a smaller, uncharged glutamine, and shows the location of the R172K mutation in context. It also features space-filling representations of α-KG and 2HG. By inhibiting 2HG production and restoring cell differentiation, AG-221 represents a targeted treatment for AML patients with the IDH2 mutation, potentially reducing mutated cell counts and improving bone marrow transplant outcomes. The model highlights AG-221's role as an inhibitor of both α-KG and NADPH within the enzyme's structure.
Faculty Sponsors
Dr. Emily Schmitt Lavin, Dr. Arthur Sikora
Project Type
Event
Location
Alvin Sherman Library
Start Date
4-2-2025 12:45 PM
End Date
4-3-2025 12:00 AM
Modeling Isocitrate Dehydrogenase 2 Mutations in Acute Myeloid Leukemia: Exploring How the Drug AG-221 Inhibits 2-hydroxyglutarate Production and Restores Blood Cell Differentiation
Alvin Sherman Library
Mutations in the Isocitrate Dehydrogenase 2 (IDH2) enzyme have been linked to acute myeloid leukemia (AML). IDH2, involved in the citric acid cycle, normally converts isocitrate to α-ketoglutarate (α-KG), using NADP+ to produce NADPH. Mutations like R140Q and R172K lead IDH2 to convert αKG into the oncometabolite 2-hydroxyglutarate (2HG), hindering blood cell differentiation and resulting in AML.
The drug AG-221 targets mutant IDH2 at an allosteric site, stabilizing the enzyme in an inactive form and preventing 2HG formation, thus alleviating AML symptoms. Most patients, however, require additional chemotherapy and often complete bone marrow transplants. A 3-D printed model based on PDB-IDs: 5I96 and 5I95 illustrates how AG-221, NADPH, and α-KG interact with the mutant IDH2 enzyme. Specific amino acids at the binding interface, including Y311, D312, Q316, L320, I319, L298, L160, and W164, are highlighted to show their interaction with AG-221.
Additionally, the model emphasizes the R140Q mutation, where the relatively larger and positively charged arginine is replaced by a smaller, uncharged glutamine, and shows the location of the R172K mutation in context. It also features space-filling representations of α-KG and 2HG. By inhibiting 2HG production and restoring cell differentiation, AG-221 represents a targeted treatment for AML patients with the IDH2 mutation, potentially reducing mutated cell counts and improving bone marrow transplant outcomes. The model highlights AG-221's role as an inhibitor of both α-KG and NADPH within the enzyme's structure.
Comments
TED-Style Talk