MGMT inhibitors—The Trinity College–Paterson Institute experience, a chemist's perception

The DNA repair protein, O6-alkylguanine-DNA alkyltransferase (MGMT) can confer resistance to the cancer chemotherapeutic effects of the class of DNA damaging drugs generally referred to as the O6-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 O6-arylmethylguanines opened up the way to make a series of O6-heteroalkylmethyl analogues of the archetypal MGMT pseudosubstrate, O6-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 O6-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.