TLK-286: a novel glutathione S-transferase-activated prodrug.

Abstract

Telik, Inc. (Palo Alto, CA, USA) is currently developing TLK-286, a novel prodrug that is preferentially activated by glutathione S-transferase P1-1 (GST-pi). TLK-286 is the lead clinical candidate from a group of rationally designed glutathione analogues designed to exploit high GST-pi levels in solid tumours and drug-resistant cell populations. This concept was based on extensive literature showing that the overexpression of GST-pi in human tumours is associated with malignancy, poor prognosis and the development of drug resistance. Thus, the selective targeting of susceptible tumour phenotypes is a strategy that should result in the release of more active drug in malignant cells compared with normal tissue, thereby achieving an improved therapeutic index. A number of published preclinical studies have confirmed the mechanism of action of this drug. In a series of Phase II clinical trials, TLK-286 was initially shown to have clinical activity and a favorable toxicity profile as a single agent in the salvage setting in ovarian, non-small cell lung, breast and colorectal cancers. Recently, Phase II trials have been reported that demonstrated TLK-286 is active and did not increase the toxicity in combination treatment regimens with standard chemotherapeutic agents, including platinums, taxanes and anthracyclines in previously treated patients with ovarian and non-small cell lung cancers, and in the first-line treatment setting in non-small cell lung cancer patients. TLK-286 is also presently under active testing in Phase III settings for non-small cell lung and ovarian cancers.

• Authors: Kenneth D Tew
• Journal: Expert opinion on investigational drugs (Expert Opin Investig Drugs) Vol. 14 Issue 8 Pg. 1047-54 (Aug 2005) ISSN: 1744-7658 [Electronic] England
• PMID: 16050796 (Publication Type: Journal Article, Review)

Chemical References

• Antineoplastic Agents
• Drugs, Investigational
• Prodrugs
• TER 286
• Glutathione Transferase
• Glutathione

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology, therapeutic use)
• Clinical Trials, Phase II as Topic (trends)
• Drugs, Investigational (chemistry, pharmacology, therapeutic use)
• Enzyme Activation (drug effects)
• Glutathione (analogs & derivatives, chemistry, pharmacology, therapeutic use)
• Glutathione Transferase (biosynthesis, chemistry)
• Humans
• Prodrugs (chemistry, pharmacology, therapeutic use)