Lomeguatrib is an O6-methylguanine-DNA-methyl-transferase (MGMT) inhibitor [1], with an IC50 value of about 6 nM to inactivate MGMT in MCF-7 cells, effectively [2].
MGMT activity is closely related to MTIC (a metabolite of dacarbazine)-mediated DNA damage [1].
Lomeguatrib sensitized MGMT-activity-bearing A375P cells to temozolomide (TMZ), but it failed to affect the effect of dacarbazine (DTIC). In other mutBRAF cells and several mutNRAS cell lines such as WM1361, similar results were obtained [1].
With one exception, patients treated with lomeguatrib showed no active or very low MGMT in PBMCs. Lomeguatrib at a dose of 20 mg resulted in 16.7 fmol/μg DNA active MGMT in a CNS-tumor-bearing patient. This patient showed a percentage of 25% for inactive tumor MGMT. This percentage was lower than that in the other two CNS patients with lomeguatrib at the same dose. Different tumor types showed remarkable differences in total tumor MGMT. Prostate cancers had the highest (554 ± 404 fmol/mg protein), CNS tumors had the lowest (89.9 ± 44.5 fmol/mg protein), and colorectal tumors had intermediate levels of total protein (244 ± 181 fmol/mg protein). In the colorectal cancer, the primary CNS tumor, and the prostate cancer of patients, increasing lomeguatrib doses resulted in increasing inactive MGMT proportions [3].
References:
[1]. Imanol Arozarena, Ibai Goicoechea, Oihane Erice, et al. Differential chemosensitivity to antifolate drugs between RAS and BRAF melanoma cells. Molecular Cancer, 2014, 13:154.
[2]. M Clemons, J Kelly, AJ Watson, et al. O6-(4-bromothenyl)guanine reverses temozolomide resistance in human breast tumour MCF-7 cells and xenografts. British Journal of Cancer, 2005, 93:1152-1156.
[3]. Amanda J. Watson, Ami Sabharwal, Mary Thorncroft, et al. Tumor O6-methylguanine-DNA Methyltransferase Inactivation by Oral Lomeguatrib. Clinical Cancer Research, 2010, 16(2):743-9.
| Physical Appearance | A solid |
| Storage | Store at -20°C |
| M.Wt | 326.17 |
| Cas No. | 192441-08-0 |
| Formula | C10H8BrN5OS |
| Solubility | ≥50mg/mL in DMSO with gentle warming |
| Chemical Name | 6-[(4-bromothiophen-2-yl)methoxy]-7H-purin-2-amine |
| SDF | Download SDF |
| Canonical SMILES | C1=C(SC=C1Br)COC2=NC(=NC3=C2NC=N3)N |
| Shipping Condition | Evaluation sample solution : ship with blue ice.All other available size: ship with RT , or blue ice upon request |
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. |
| Description | Lomeguatrib is a potent inhibitor of O6-alkylguanine-DNA-alkyltransferase with IC50 of 5 nM. | |||||
| Targets | O6-alkylguanine-DNA-alkyltransferase | |||||
| IC50 | 5 nM | |||||
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Chemical structure
Related Biological Data
Related Biological Data
Abstract
The combination therapy of lomeguatrib and TMZ decreased MGMT expression, increased p53 expression and DNA fragmentation and induced apoptosis in primary GBM cell cultures and glioma cell lines without affectinf MGMT methylation and cell cycle, where the sensitivity to the therapy was associated with the structure of MGMT methylation.
Abstract
The combination of lomegutrin and TMZ decreased MGMT expression, increased p53 expression and induced apoptosis without affecting cell cycle in AA cell lines, where lomeguatrib enhanced the anti-AA activity of TMZ.
Abstract
The combination of lomeguatrib, which depletes MGMT, and dacarbazine has been assessed in a phase I trial.
Abstract
The combination of lomeguatrip and irinotecan has been assessed for MTD, safety, toxicity and clinical pharmacology in patients with metastatic cancer.
Abstract
The minimal dosage of lomeguatrib to neutralize MGMT activity for 12 hours has been determined in patients with prostate, CNS and colorectal cancer.