MGMT inhibitors--The Trinity College-Paterson Institute experience, a chemist's perception.
The DNA repair protein, O(6)-alkylguanine-DNA alkyltransferase (MGMT) can confer resistance to the cancer chemotherapeutic effects of the class of DNA damaging drugs generally referred to as the O(6)-alkylating agents. Inactivation of MGMT is thus a practical approach to improving the efficacy of such agents. An account is given of the collaboration between groups at Trinity College, Dublin and the Paterson Institute, Manchester which led to the development of the MGMT inactivating drug, Patrin (PaTrin-2, Lomeguatrib). The development of a simpler method of synthesis of O(6)-arylmethylguanines opened up the way to make a series of O(6)-heteroalkylmethyl analogues of the archetypal MGMT pseudosubstrate, O(6)-methylguanine. Of these, the furfuryl and thenyl compounds were the most active against recombinant Human MGMT in an in vitro assay. The 4-bromothenyl derivative was chosen for clinical trial as the most active compound. The MGMT active site tolerates O(6)-substituted guanines where the side chain can be quite large, but does not tolerate those with an aromatic or heteroaromatic ring with an 'ortho' substituent.
McMurry
T Brian H
TB
School of Chemistry, Trinity College, Dublin 2, Ireland. tmcmurry@tcd.ie
D000818:Animals; D003299:Cooperative Behavior; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors*; D045643:DNA Repair Enzymes / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004739:England; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000266:history / Q000494:pharmacology*; D049673:History, 20th Century; D049674:History, 21st Century; D006801:Humans; D066298:In Vitro Techniques; D007494:Ireland; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors*; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry / Q000266:history / Q000494:pharmacology; D013329:Structure-Activity Relationship; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D011687:Purines; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D019853:O(6)-Methylguanine-DNA Methyltransferase; D045643:DNA Repair Enzymes; C521206:lomeguatrib