Large-Scale Chemical Space Exploration Identifies DE19725241 as a Candidate Fat Mass and Obesity-Associated Protein-Targeting Compound with Selective Activity in Pancreatic Cancer Cells

Abstract

Background: Fat mass and obesity-associated protein (FTO), an epitranscriptomic regulator, has been implicated in cancer progression and immune regulation but the therapeutic relevance in pancreatic cancer is unclear.

Methods: TCGA and GTEx transcriptomic datasets were analyzed to evaluate FTO expression and prognostic associations in pancreatic cancer. Candidate FTO-targeting compounds were identified by active learning-assisted virtual screening of > 22 million compounds. The lead candidate, DE19725241, was further assessed by binding pose metadynamics, molecular dynamics simulations in multiple environments, MM/GBSA calculations, and in vitro testing in three pancreatic cancer cell lines and one normal pancreatic epithelial cell line.

Results: FTO was overexpressed in pancreatic tumors and associated with poorer overall survival. DE19725241 showed favorable predicted interactions with FTO, particularly with ARG-96, TYR-108, and GLU-234, and exhibited moderate but selective antiproliferative activity in pancreatic cancer cells.

Conclusions: DE19725241 represents a potential early-stage scaffold for developing FTO-targeted strategies in pancreatic cancer.

Keywords

Active learning-assisted virtual screening / ADMET / CCK-8 / chemical space library / chemistry / FTO-targeting compound / medicinal chemistry / molecular dynamics simulation / pancreatic cancer / transcriptomic analysis

References

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