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Inhibition of XPO-1 Mediated Nuclear Export through the Michael-Acceptor Character of Chalcones

Marta Gargantilla1, José López-Fernández1, Maria-Jose Camarasa1

  • 1Instituto de Química Médica (IQM, CSIC) c/Juan de la Cierva 3, 28006 Madrid, Spain.

Pharmaceuticals (Basel, Switzerland)
|November 27, 2021
PubMed

Insights

Chalcone derivatives were synthesized and evaluated as reversible covalent inhibitors of exportin-1 (XPO1). These compounds show antiproliferative activity, targeting XPO1

Area of Science:

  • Medicinal Chemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Exportin-1 (XPO1, also known as CRM1) is a nuclear export receptor crucial for transporting proteins with leucine-rich nuclear export signals (NES) out of the nucleus.
  • XPO1 is implicated in various diseases, including hematological malignancies, cancer drug resistance, inflammation, neurodegeneration, and viral infections, making it a significant therapeutic target.
  • Current XPO1 inhibitors, like leptomycin B and SINE compounds, exert their effect through covalent interaction with Cys528 in the XPO1 NES-binding cleft.

Purpose of the Study:

  • To synthesize and characterize novel chalcone derivatives as potential reversible covalent inhibitors of XPO1.
  • To investigate the antiproliferative effects of these chalcones in cancer cell lines and their correlation with XPO1 inhibition.
  • To elucidate the molecular mechanism of inhibition, focusing on the role of Cys528 in the XPO1 NES-binding cleft.

Main Methods:

  • Synthesis of two series of chalcone derivatives designed to react with thiol groups.
  • Assessment of thiol reactivity using glutathione (GSH) and analysis of adduct stability (reversible hetero-Michael addition).
  • Evaluation of antiproliferative activity against a panel of cancer cell lines and direct XPO1 inhibition assays.
  • Testing against a Cys528-mutated XPO1 Jurkat cell line (XPO1C528S) to confirm the target.
  • Molecular modeling using the CovDock computational tool to study interactions within the XPO1 NES-binding cleft.

Main Results:

  • Chalcones formed reversible hetero-Michael adducts with GSH, indicating potential for reversible covalent binding.
  • A strong correlation was observed between the antiproliferative activity of chalcone derivatives and their efficacy as XPO1 inhibitors.
  • Prototype chalcones 9 and 10 did not inhibit cargo export in XPO1C528S cells, confirming Cys528 as the critical target residue.
  • Computational studies provided insights into the molecular interactions of chalcones within the XPO1 NES-binding cleft.

Conclusions:

  • Chalcone derivatives represent a promising class of reversible covalent inhibitors targeting XPO1.
  • The observed antiproliferative effects are directly linked to the inhibition of XPO1, specifically through interaction with Cys528.
  • These findings support the therapeutic potential of chalcone-based XPO1 inhibitors for various diseases.
Keywords:
CovDockanticancer activitychalconescovalent bindingexportin-1

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