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-π). TLK-286 is the lead clinical candidate from a group of rationally designed glutathione analogues designed to exploit high GST-π levels in solid tumours and drug-resistant cell populations. This concept was based on extensive literature showing that the overexpression of GST-π 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.

Keywords::

• alkylating agent
• glutathione
• glutathione S-transferase
• non-small cell lung cancer
• ovarian cancer
• prodrug