TLK-286: a novel glutathione S-transferase-activated prodrug.
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.
Tew
Kenneth D
KD
Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, 173 Ashley Avenue, PO Box 250505, Charleston, SC 29425, USA. tewk@musc.edu
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017322:Clinical Trials, Phase II as Topic / Q000639:trends; D015507:Drugs, Investigational / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D004789:Enzyme Activation / Q000187:drug effects; D005978:Glutathione / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000737:chemistry*; D006801:Humans; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D015507:Drugs, Investigational; D011355:Prodrugs; C107479:TER 286; D005982:Glutathione Transferase; D005978:Glutathione