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Rational Development of Activatable Prodrugs of the GSTP1 Inhibitor NBDHEX: Turn-On NIR Fluorogenic Drug Delivery

Rahul Kesarwani1, Nikita Pal1, Dorothy Das2

  • 1Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India.

Journal of Medicinal Chemistry
|July 2, 2026
PubMed

Insights

A new prodrug, RK-251, effectively targets cancer cells by releasing the drug NBDHEX in response to reactive oxygen species (ROS). This targeted delivery enhances anticancer activity and allows for fluorescence imaging of drug release in vivo.

Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Oncology

Background:

  • Glutathione-S-transferase pi (GSTP1) is overexpressed in cancer cells and inactivates anticancer drugs.
  • NBDHEX is a potent GSTP1 inhibitor but has poor solubility and bioavailability.
  • Developing targeted drug delivery systems is crucial for improving cancer therapy.

Purpose of the Study:

  • To design and synthesize a reactive oxygen species (ROS)-responsive fluorogenic prodrug of NBDHEX.
  • To evaluate the prodrug's efficacy in inhibiting GSTP1 and its anticancer activity.
  • To assess the prodrug's activation mechanism, fluorescence properties, and in vivo safety.

Main Methods:

  • Synthesis of the ROS-responsive prodrug RK-251 by conjugating NBDHEX with a QCy7 fluorophore and a ROS-sensitive unit.
  • In vitro evaluation of GSTP1 inhibition, ROS-mediated drug release, and anticancer activity against cancer cell lines.
  • In vivo studies using zebrafish embryos to assess fluorescence imaging and toxicity.

Main Results:

  • RK-251 demonstrated ROS-mediated uncaging of NBDHEX with turn-on NIR fluorescence and potent GSTP1 inhibition.
  • The prodrug exhibited significant anticancer activity against triple-negative breast cancer cells.
  • In vivo studies in zebrafish confirmed endogenous ROS-mediated activation and QCy7 release without toxicity.

Conclusions:

  • RK-251 is an effective ROS-responsive fluorogenic prodrug for targeted cancer therapy.
  • The prodrug offers a dual modality of therapeutic action and fluorescence imaging.
  • RK-251 shows translational potential for cancer treatment and diagnostics.

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