Mechanism of Glutathione Transferase P1-1-Catalyzed Activation of the Prodrug Canfosfamide (TLK286, TELCYTA)

• Type: Article in International Scientific Journal
• Date: 2013

Authors

Daniel F A R Dourado (Author) Other; Pedro Alexandrino Fernandes (Author) FCUP; Maria Joao Ramos (Author) FCUP; Bengt Mannervik (Author) Other

Journal

Title: Biochemistry

Vol. 52

Pages: 8069-8078

ISSN: 0006-2960

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 27 Citations

Scopus - 29 Citations

Scientific classification

FOS: Natural sciences > Biological sciences

Other information

Authenticus ID: P-008-GT4

DOI: 10.1021/bi4005705

Abstract (EN): Canfosfamide (TLK286, TELCYTA) is a prodrug that upon activation by glutathione transferase P1-1 (GST P1-1) yields an anticancer alkylating agent and a glutathione derivative. The rationale underlying the use of TLK286 in chemotherapy is that tumor cells overexpressing GST P1-1 will be locally exposed to the released alkylating agent with limited collateral toxicity to the surrounding normal tissues. TLK286 has demonstrated clinical effects in phase II and III clinical trials for the treatment of malignancies, such as ovarian cancer, nonsmall cell lung cancer, and breast cancer, as a single agent and in combination with other chemotherapeutic agents. In spite of these promising results, the detailed mechanism of GST P1-1 activation of the prodrug has not been elucidated. Here, we propose a mechanism for the TLK286 activation by GST P1-1 on the basis of density functional theory (DFT) and on potential of mean force (PMF) calculations. A catalytic water molecule is instrumental to the activation by forming a network of intermolecular interactions between the active-site Tyr7 hydroxyl and the sulfone and COO- groups of TLK286. The results obtained are consistent with the available experimental kinetic data and provide an atomistic understanding of the TLK286 activation mechanism.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 10