Mechanism of glutathione transferase P1-1-catalyzed activation of the prodrug canfosfamide (TLK286, TELCYTA).
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.
REQUIMTE/Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto , Rua do Campo Alegre s/n, 4169-007 Porto, Portugal.
Daniel F A R
DF
Dourado
Pedro Alexandrino
PA
Fernandes
Maria João
MJ
Ramos
Bengt
B
Mannervik
D005978:Glutathione / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D051549:Glutathione S-Transferase pi / Q000378:metabolism*; D015394:Molecular Structure; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism*
D011355:Prodrugs; C107479:TER 286; D051549:Glutathione S-Transferase pi; D005978:Glutathione