A Novel Allosteric Inhibitor Targeting IMPDH at Y233 Overcomes Resistance to Tyrosine Kinase Inhibitors in Lymphoma.

ABSTRACT:

Background/objective

Oncogenic tyrosine kinases (TKs) such as ALK and SRC promote cancer progression, but their effects on metabolic enzymes are still not well understood. This study examines how TK signaling regulates inosine monophosphate dehydrogenase 2 (IMPDH2), a rate-limiting enzyme in purine biosynthesis, and assesses its potential as a therapeutic target.

Methods

Phosphoproteomic screening and in vitro kinase assays were used to identify phosphorylation sites on IMPDH2. Lipid-binding assays explored the role of phosphatidylinositol 3-phosphate (PI3P) in IMPDH2 regulation. Structure-based virtual screening discovered small-molecule allosteric inhibitors, which were tested in lymphoma cell models, including ALK and BTK-inhibitor resistant lines.

Results

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SUBMITTER: Pattabiraman N 

PROVIDER: S-EPMC12563536 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature