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Area of Science:

  • Biochemistry
  • Pharmacology
  • Oncology

Background:

  • Carboxylesterase 2 (CES2) is key in converting Irinotecan (CPT-11) to its active form, SN-38.
  • High CES2 activity can lead to toxic SN-38 levels and severe side effects, like diarrhea, in pancreatic ductal adenocarcinoma (PDAC) patients.
  • Inhibiting CES2 offers a strategy to control CPT-11 pharmacokinetics and SN-38 production.

Purpose of the Study:

  • To discover and validate small-molecule inhibitors of CES2.
  • To identify compounds that can mitigate CPT-11 toxicity by modulating SN-38 generation.
  • To explore CES2 inhibition as a therapeutic approach for PDAC treatment.

Main Methods:

  • High-throughput screening to identify CES2 inhibitors.
  • Dose-response assays and counter-screening for validation and selectivity.
  • Cell-based assays to confirm CES2 inhibition and cell permeability.
  • Enzyme inhibition assays with purified CES2 and CPT-11.
  • Assessment of inhibitor efficacy in preventing CPT-11-induced cell death in PDAC cells.

Main Results:

  • 18 small-molecule CES2 inhibitors were discovered through high-throughput screening.
  • 16 inhibitors demonstrated selectivity for CES2 and inhibited the enzyme in cellular assays.
  • Inhibitors successfully blocked CPT-11 conversion by purified CES2.
  • The top five inhibitors protected PDAC cells from CPT-11-mediated cell death.
  • Three inhibitors exhibited tight-binding mechanisms with high affinity.

Conclusions:

  • Novel, selective small-molecule CES2 inhibitors have been identified.
  • These inhibitors effectively block CPT-11 conversion to SN-38 in vitro and in cellulo.
  • The identified inhibitors show promise in protecting against CPT-11 toxicity and warrant further investigation for PDAC therapy.