Lomeguatrib, an inhibitor of DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) with IC50 of 0.009 μM in cell-free extracts from HeLa S3 cells, is a modified guanine base.
MGMT (O6-methylguanine-DNA methyltransferase) is an important DNA repair protein for defending alkylating agents through transferring the alkyl adducts onto a cysteine on the active site of MGMT[3]. Lomeguatrib is an MGMT inhibitor with IC50 of around 6 nM in MCF-7 cells[4]. The U-118 MG cells were treated with a combination treatment of temozolomide with 50 μM of lomeguatrib. The MGMT expression level was decreased and the p53 expression level was increased compared with control as determined by RT-qPCR[5]. In a nude mice bearing human melanoma xenografts model, the lomeguatrib was given at a dose of 20 mg/kg i.p. one hour prior to the temozolomide injection once daily for five days. The combinded treatment of temozolomide and lomeguatrib increased the antitumor activity as the tumour growth was delayed with less toxicity[6].
作用机制
The lomeguatrib act as pseudosubstrates to deplete MGMT. It can covalently transfer the bromothenyl group to the active site cysteine on the protein after ubiquitin-dependent proteolysis[7].
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