Related Experiment Video

Updated: Aug 11, 2026

Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission
07:16

Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission

Published on: August 16, 2018

ZD9331: discovery to clinical development

T S Benepal1, I Judson

  • 1Royal Marsden Hospital NHS Trust, Sutton, Surrey UK. tim.benepal@rmh.nthames.nhs.uk

Anti-Cancer Drugs
|December 23, 2004
PubMed

Insights

ZD9331, a novel thymidylate synthase inhibitor, shows promise in treating various cancers without polyglutamation. This cancer drug may reduce toxicity and overcome resistance, particularly in ovarian, pancreatic, and gastric cancers.

Area of Science:

  • Oncology
  • Pharmacology
  • Cancer Therapeutics

Background:

  • Thymidylate synthase (TS) is a validated target in cancer therapy.
  • Previous TS inhibitors, like raltitrexed, require polyglutamation for activity.
  • Reduced expression of folylpolyglutamate synthetase (FPGS) can lead to resistance against polyglutamatable drugs.

Purpose of the Study:

  • To evaluate ZD9331, a third-generation TS inhibitor designed for non-polyglutamation.
  • To overcome resistance mechanisms associated with FPGS.
  • To potentially reduce toxicities linked to polyglutamation and drug retention.

Main Methods:

  • Preclinical studies assessed ZD9331 transport via reduced folate carrier and alpha-folate receptor.
  • In vivo studies demonstrated broad anti-cancer activity.
  • Extensive Phase I clinical trials were conducted across various administration schedules.

Main Results:

  • ZD9331 demonstrated promising activity in platinum-refractory relapsed ovarian, pancreatic, and gastric cancers.
  • The drug is transported by both reduced folate carrier and alpha-folate receptor.
  • Monotherapy and combination studies showed encouraging outcomes.

Conclusions:

  • ZD9331 represents a novel approach to TS inhibition, potentially offering improved efficacy and safety.
  • Patient selection based on folate transport and FPGS status may enhance therapeutic potential.
  • Further investigation is warranted to determine the full clinical utility of ZD9331.

More Related Videos

NMR-Based Fragment Screening in a Minimum Sample but Maximum Automation Mode09:19

NMR-Based Fragment Screening in a Minimum Sample but Maximum Automation Mode

Published on: June 4, 2021

Nano-Differential Scanning Fluorimetry for Screening in Fragment-based Lead Discovery06:26

Nano-Differential Scanning Fluorimetry for Screening in Fragment-based Lead Discovery

Published on: May 16, 2021

Related Concept Videos

NF-κB-dependent Signaling Pathway02:26

NF-κB-dependent Signaling Pathway

The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
Clinical Trials01:16

Clinical Trials

Clinical trials are prospective experimental studies conducted on humans to determine the safety and efficacy of treatments, drugs, diet methods, and medical devices. Using statistics in clinical trials enables researchers to derive reasonable and accurate conclusions from the collected data, allowing them to make wise decisions in uncertain situations. In medical research, statistical methods are crucial for preventing errors and bias.
There are four phases in a clinical trial. A phase one...
Drug Discovery: Overview01:26

Drug Discovery: Overview

Drug discovery is a multifaceted process involving extensive screening, testing, and optimization of lead compounds to identify potential new drugs for therapeutic use. It combines several approaches, including screening large numbers of natural products, chemical modification of known active molecules, identification of new drug targets, and rational design based on biological mechanisms and drug-receptor structure. These approaches are carried out in both academic research laboratories and...
Clinical Trials: Overview01:11

Clinical Trials: Overview

Clinical development focuses on how the drug will interact with the human body and encompasses four key phases of clinical trials, each serving a specific purpose in assessing the safety and effectiveness of new drugs. These phases overlap and build upon one another. Phase I involves a small group of healthy volunteers (typically 20-80 individuals) or, in cases where significant toxicity is expected, patients with the targeted disease, such as cancer or AIDS. The volunteers are tested for...
Preclinical Development: Overview01:28

Preclinical Development: Overview

Preclinical development consists of a series of tests that ensure the safety and efficacy of a new therapeutic compound before it is tested in humans. There are four main phases to this process. First, safety pharmacology tests are conducted to ensure the drug does not produce any acutely harmful effects. These tests examine parameters such as bronchoconstriction, cardiac dysrhythmias, blood pressure changes, and ataxia. Next, preliminary toxicological testing is performed to determine the...
Pharmacogenomics: Identification of New Drug Targets01:29

Pharmacogenomics: Identification of New Drug Targets

Advances in genomics have profoundly influenced drug discovery by increasing both the speed and accuracy of pharmaceutical development. Pharmacogenomics, which examines how genetic variation influences drug response, facilitates the identification of novel therapeutic targets and enables patient stratification for personalized treatment. These strategies contribute to improved drug efficacy, minimized adverse effects, and more efficient clinical trial design.Mapping genetic differences...