title: S-alkylthiolation of O6-methylguanine-DNA-methyltransferase (MGMT) to sensitize cancer cells to anticancer therapy.
abstract: O6-methylguanine DNA methyltransferase/O6-alkylguanine DNA alkyltransferase (MGMT/AGT) removes alkyl adducts from the O6-position of guanine in DNA. Expression of MGMT in human cancers has been associated with resistance to therapies using alkylating agents. MGMT promoter methylation regulates its expression and response to alkylating agents. A combination of O6-benzylguanine-based inhibitors of MGMT with alkylating agents improved the efficacy. However, this is associated with enhanced cytotoxicity and the induction of GC to AT transition mutations presumably also in progenitor/stem cells. A few recent studies have described analogs of O6-benzylguanine targeting defined pathways of cancer cells that can be used to improve the selectivity of O6-benzylguanine-based inhibitors for cancer cells. Therefore, MGMT inhibitor targeting represents a reliable strategy for improving cancer therapy with alkylating agents.
authors.affiliation: Institute of Chemical Sciences and Engineering, Swiss Institute of Technology of Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Juillerat
authors.forename: Lucienne
authors.initials: L
authors.lastname: Juillerat-Jeanneret
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006147:Guanine / Q000031:analogs & derivatives / Q000627:therapeutic use; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004791:Enzyme Inhibitors; C064976:O(6)-benzylguanine; D006147:Guanine; D019853:O(6)-Methylguanine-DNA Methyltransferase