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Related Experiment Videos

Anticancer drug development at Lilly Research Laboratories

H L Pearce1

  • 1Lilly Research Laboratories, Indianapolis, IN, USA.

Annals of Oncology : Official Journal of the European Society for Medical Oncology
|January 1, 1995
PubMed
Summary
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Lilly

Area of Science:

  • Oncology
  • Pharmacology
  • Biochemistry

Background:

  • Over 15 years, cancer drug discovery at Lilly has evolved from syngeneic murine models to more rational, biochemically-driven approaches.
  • Early methods identified difluoronucleoside antimetabolites, diarylsulfonylureas, and folate-based enzyme inhibitors.
  • Current research focuses on folate metabolism for targeted cancer therapies.

Purpose of the Study:

  • To refine cancer drug discovery through a deeper understanding of folate metabolism and drug interactions.
  • To develop novel oncolytic agents with designed cellular selectivities.
  • To explore folate receptor binding and polyglutamation for predicting drug efficacy and toxicity.

Main Methods:

  • Utilizing syngeneic murine solid tumor models for initial agent identification.

Related Experiment Videos

  • Investigating structure-activity relationships of folate antimetabolites.
  • Studying folate transport, processing, and enzyme inhibition mechanisms.
  • Analyzing folate receptor binding properties and polyglutamation via folylpolyglutamate synthase.

    • Main Results:

    • Identification of new drug classes including difluoronucleoside antimetabolites and folate-based enzyme inhibitors.
    • Development of a rational approach to drug discovery based on biochemical pathways.
    • Preclinical demonstration of broad activity for inhibitors of purine biosynthesis and thymidylate synthesis in human tumor xenografts.

    Conclusions:

    • A comprehensive understanding of folate metabolism enables rational design of targeted cancer therapies.
    • Folate-based drug discovery serves as a model for other biochemically targeted programs.
    • Inhibitors targeting purine biosynthesis and thymidylate synthesis show promise and are in clinical testing.