Related Experiment Video

Updated: May 30, 2026

Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors
08:45

Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors

Published on: July 17, 2020

Tyrosyl-DNA Phosphodiesterase 1 (Tdp1) inhibitors

Shar-yin N Huang1, Yves Pommier, Christophe Marchand

  • 1National Cancer Institute , Center for Cancer Research, Laboratory of Molecular Pharmacology , National Institutes of Health , Bethesda, MD, 20892 , USA.

Expert Opinion on Therapeutic Patents
|August 17, 2011
PubMed

Insights

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) inhibitors show promise for cancer therapy. By blocking DNA repair, these inhibitors can enhance the effectiveness of common chemotherapy drugs, improving patient outcomes.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Topoisomerase I (Top1) inhibitors are crucial in cancer treatment, causing stalled Top1 cleavage complexes (Top1cc).
  • Combination chemotherapy using DNA repair inhibitors may enhance responses to Top1-targeting drugs.
  • Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a key enzyme in repairing Top1cc.

Purpose of the Study:

  • To review structure-activity relationships of reported Tdp1 inhibitors.
  • To explore the potential of Tdp1 inhibitors in combination cancer chemotherapy.
  • To highlight the importance of understanding Tdp1-inhibitor interactions for drug design.

Main Methods:

  • Literature review of Tdp1 inhibitors and their structure-activity relationships.
  • Analysis of Tdp1's role in repairing Top1-induced DNA damage.
  • Discussion of potential synergistic effects with various chemotherapeutic agents.

Main Results:

  • Tdp1 inhibitors are effective in hydrolyzing DNA adducts, including Top1-derived peptides and 3'-phosphoglycolates.
  • Tdp1 inhibitors are expected to synergize with Top1 inhibitors, Top2 inhibitors, bleomycin, and DNA alkylating agents.
  • Structure-activity relationship studies provide insights into Tdp1 inhibitor design.

Conclusions:

  • Tdp1 inhibitors represent a promising strategy for enhancing cancer chemotherapy efficacy.
  • Further research into in vivo Top1cc repair and Tdp1-inhibitor interactions is essential for rational drug design.
  • Developing effective Tdp1 inhibitors could broaden therapeutic options for various cancers.

More Related Videos

Screening for Thermotoga maritima Membrane-Bound Pyrophosphatase Inhibitors09:11

Screening for Thermotoga maritima Membrane-Bound Pyrophosphatase Inhibitors

Published on: November 23, 2019

Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors06:07

Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors

Published on: August 5, 2022

Related Concept Videos

Inhibitors of Bacterial DNA Synthesis01:28

Inhibitors of Bacterial DNA Synthesis

Bacterial pathogens depend on precise and efficient DNA replication to sustain infection. Two type II topoisomerases—DNA gyrase and topoisomerase IV—are critical to this process, as they resolve DNA supercoiling and unlink chromosomes during replication. Fluoroquinolones, synthetic derivatives of quinolones, exploit this mechanism by stabilizing the transient DNA–enzyme cleavage complex, preventing strand religation, and causing lethal double-strand breaks. These antibiotics are selectively...
Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase01:11

Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase

Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
Transducer Mechanism: Enzyme-Linked Receptors01:27

Transducer Mechanism: Enzyme-Linked Receptors

Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
Dipeptidyl Peptidase 4 Inhibitors01:23

Dipeptidyl Peptidase 4 Inhibitors

Dipeptidyl peptidase 4 (DPP-4) is a serine protease widely distributed in the body. It's involved in the inactivation of GLP-1 and GIP hormones, which are crucial for insulin regulation. DPP-4 inhibitors, such as sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), alogliptin (Nesina), and vildagliptin (Galvus), help increase the proportion of active GLP-1, enhancing insulin secretion. These inhibitors work by competitively binding to DPP-4. This binding causes a significant...
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

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...
Translesion DNA Polymerases02:10

Translesion DNA Polymerases

Translesion (TLS) polymerases rescue stalled DNA polymerases at sites of damaged bases by replacing the replicative polymerase and installing a nucleotide across the damaged site. Doing so, TLS allows additional time for the cell to repair the damage before resuming regular DNA replication.
TLS polymerases are found in all three domains of life - archaea, bacteria, and eukaryotes. Of the different classes of TLS polymerases, members of the Y family are fitted with specialized structures that...