Description
Lomeguatrib (192441-08-0) is a potent (IC50?= 9 nM) inhibitor of O6-Methylguanine-DNA Methyltransferase (MGMT), an important DNA repair protein.1?It is currently being investigated in cancers that have acquired resistant to the chemotherapeutic temozolomide2-5, as well as other chemotherapeutics6,7.
Uses
O6-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein which removes an alkyl group from the O6 position on guanine in an autoinactivating reaction. Although important in normal DNA repair, this reaction confers resistance to treatments that use O6-alkylating agents to produce cytotoxicity, e.g., in cancer. Lomeguatrib is a modified quanine base which acts as a pseudosubstrate inactivator of MGMT (IC50 = ~3 nM). A non-toxic compound, lomeguatrib completely inactivates MGMT in human prostate and colorectal tumors when given as a single 120 mg oral dose and in primary central nervous system cancers at 160 mg.
in vivo
Lomeguatrib (20?mg/kg i.p.) completely inactivates MGMT within 2?h, but shows no significant effect on tumor growth in MCF-7 xenografts[2].
IC 50
MGMT: 6 nM (IC50, in MCF-7 cells); MGMT: 9 nM (IC50)
References
1) Reinhard?et al.?(2001),?Monosaccharide-Linked Inhibitors of O6-Methylguanine-DNA Methyltransferase (MGMT): Synthesis, Molecular Modeling, and Structure-Activity Relationships; J. Med. Chem.?44?4050
2) Barvaux?et al.?(2004),?Sensitization of a human ovarian cancer cell line to temozolomide by simultaneous attenuation of the Bcl-2 antiapoptotic protein and DNA repair by O6-alkylguanine-DNA alkyltransferase: Mol. Cancer Ther.?3?1215
3) Gumbrell?et al.?(2006),?Lomeguatrib, a potent inhibitor of O6-alkylguanine-DNA-alkyltransferase: phase I safety, pharmacodynamic, and pharmacokinetic trial and evaluation in combination with temozolomide in patients with advanced solid tumors: Clin. Cancer Res.?12?1577
4) Watson?et al.?(2009),?O(6)-methylguanine-DNA methyltransferase depletion and DNA damage in patients with melanoma treated with temozolomide alone or with lomeguatrib: Br. J. Cancer?100?1250
5) Taspinar?et al.?(2013),?Effect of lomeguatrib-temozolomide combination of MGMT promoter methylation and expression in primary glioblastoma tumor cells: Tumour Biol.?34?1935
6) Sabharwal?et al.?(2010),?A phase I trial of lomeguatrib and irinotecan in metastatic colorectal cancer: Cancer Chemother. Pharmacol.?66?829
7) Tawbi?et al.?(2011),?Inhibition of DNA repair with MGMT pseudosubstrates: phase I study of lomeguatrib in combination with dacarbazine in patients with advanced melanoma and other solid tumors: Br. J. Cancer?105?773
