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Related Concept Videos

Targeted Cancer Therapies02:57

Targeted Cancer Therapies

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The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
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The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
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Related Experiment Video

Updated: Jul 27, 2025

Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics
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A Bifunctional PARP-HDAC Inhibitor with Activity in Ewing Sarcoma.

Louise Ramos1,2,3, Sarah Truong2,3, Beibei Zhai1,2,3

  • 1Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|June 6, 2023
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Summary

A novel bifunctional inhibitor, kt-3283, targets both PARP and HDAC enzymes, showing enhanced efficacy against Ewing sarcoma. This dual-action molecule offers a promising single-drug strategy for treating this rare cancer.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Histone deacetylase (HDAC) inhibition can induce "BRCAness," a state of synthetic lethality in cancers with proficient DNA repair.
  • Combining HDAC and poly (ADP-ribose) polymerase (PARP) inhibitors is a strategy for cancers resistant to single-agent PARP inhibitors (PARPi).

Purpose of the Study:

  • To report the development and characterization of a novel bifunctional inhibitor, kt-3283, with dual PARP1/2 and HDAC activity.
  • To evaluate the efficacy of kt-3283 in Ewing sarcoma models.

Main Methods:

  • Assays for PARP1/2, HDAC activity, and PAR formation.
  • Cytotoxicity, cell-cycle, and DNA damage assessments (γH2AX, comet assay).
  • Evaluation of metastatic potential using an ex vivo pulmonary metastasis assay (PuMA).

Main Results:

  • Kt-3283 demonstrated superior cytotoxicity compared to FDA-approved PARPi (olaparib) and HDAC inhibitors (vorinostat) in Ewing sarcoma models.
  • Kt-3283 induced significant S and G2-M cell-cycle arrest and elevated DNA damage at nanomolar concentrations.
  • Kt-3283 inhibited Ewing sarcoma cell colonization in the ex vivo PuMA model.

Conclusions:

  • Kt-3283 provides preclinical justification for a clinical trial of dual PARP and HDAC inhibition in Ewing sarcoma.
  • This study presents proof-of-concept for a single-molecule bifunctional therapeutic strategy targeting Ewing sarcoma.