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Anticancer drug development at Lilly Research Laboratories
1Lilly Research Laboratories, Indianapolis, IN, USA.
Background:
The discovery and clinical development of new drugs to treat cancer at Lilly Research Laboratories has undergone significant change during the past 15 years. During the early 1980s drug discovery relied heavily on a panel of syngeneic murine solid tumour models to identify new agents for clinical trial. New classes of oncolytic agents identified by this methodology include the difluoronucleoside antimetabolites, diarylsulfonylureas, and a series of folate-based enzyme inhibitors. Within the folate-based discovery programme at Lilly, a broad understanding of the structure activity relationships of folate antimetabolites and the biochemical basis of folate transport, processing, and enzyme inhibition has enabled a more rational approach for drug discovery.
Current Studies:
Folate receptor binding properties are being studied to predict tumour sensitivities and tissue toxicities. This information, together with knowledge of a compound's ability to undergo polyglutamation via the enzyme folylpolyglutamate synthase, assist in the more rational selection of agents with designed cellular selectivities. Ultimately, the complex metabolic pathways involving folate metabolism provide numerous targets for enzyme inhibition. Inhibitors of purine biosynthesis and thymidylate synthesis have demonstrated broad activity in preclinical models of disease including several human tumour xenografts, and are undergoing clinical testing. The folate-based drug discovery programme serves as a model for other biochemically based drug discovery programs including those based in drug resistance, signal transduction and cell cycle control.
Insights
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.
- 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.