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Lomeguatrib

Lomeguatrib is  a potent Inhibitor of O6-Alkylguanine-DNA-Alkyltransferase. Lomeguatrib is also a nontoxic low-molecular weight pseudosubstrate that has the ability to inactivate MGMT.

Lomeguatrib is  an O(6)-methylguanine-DNA methyltransferase inactivator, which was evaluated in an extended dosing regimen with temozolomide, designed according to pharmacodynamic data from previous studies. Patients with unresectable stage 3 or 4 cutaneous or unknown primary melanoma metastases were treated with lomeguatrib 40 mg, b.i.d. for 10 or 14 days and temozolomide 75-100 mg m(-2) on days 1-5. Drugs were administered orally with cycles repeated every 28 days, for up to six cycles. Only limited clinical activity was seen, suggesting no advantage for this regimen over conventional temozolomide administration in the treatment of melanoma. see: http://www.ncbi.nlm.nih.gov/pubmed/19367282.

In a phase II trial, to evaluate the tumour response to lomeguatrib and temozolomide (TMZ) administered for 5 consecutive days every 4 weeks in patients with metastatic colorectal carcinoma. Patients with stage IV metastatic colorectal carcinoma received lomeguatrib (40 mg) and TMZ (50-200 mg m(-2)) orally for 5 consecutive days every 4 weeks. Response was determined every two cycles. Results showed that this combination of lomeguatrib and TMZ is not efficacious in metastatic colorectal cancer. If further studies are to be performed, emerging data suggest that higher daily doses of lomeguatrib and a dosing period beyond that of TMZ should be evaluated. see http://www.ncbi.nlm.nih.gov/pubmed/18475294.

Current developer:  KuDOS Pharmaceuticals Ltd. and AstraZeneca

1: Tawbi HA, Villaruz L, Tarhini A, Moschos S, Sulecki M, Viverette F, Shipe-Spotloe J, Radkowski R, Kirkwood JM. Inhibition of DNA repair with MGMT pseudosubstrates: phase I study of lomeguatrib in combination with dacarbazine in patients with advanced melanoma and other solid tumours. Br J Cancer. 2011 Aug 2. doi: 10.1038/bjc.2011.285. [Epub ahead of print] PubMed PMID: 21811257.

2: Watson AJ, Sabharwal A, Thorncroft M, McGown G, Kerr R, Bojanic S, Soonawalla Z, King A, Miller A, Waller S, Leung H, Margison GP, Middleton MR. Tumor O(6)-methylguanine-DNA methyltransferase inactivation by oral lomeguatrib. Clin Cancer Res. 2010 Jan 15;16(2):743-9. Epub 2010 Jan 12. PubMed PMID: 20068091; PubMed Central PMCID: PMC2807621.

3: Sabharwal A, Corrie PG, Midgley RS, Palmer C, Brady J, Mortimer P, Watson AJ, Margison GP, Middleton MR. A phase I trial of lomeguatrib and irinotecan in metastatic colorectal cancer. Cancer Chemother Pharmacol. 2010 Oct;66(5):829-35. Epub 2009 Dec 29. PubMed PMID: 20039040.

4: Sabharwal A, Waters R, Danson S, Clamp A, Lorigan P, Thatcher N, Margison GP, Middleton MR. Predicting the myelotoxicity of chemotherapy: the use of pretreatment O6-methylguanine-DNA methyltransferase determination in peripheral blood mononuclear cells. Melanoma Res. 2009 Jun 25. [Epub ahead of print] PubMed PMID: 19561552.

5: Watson AJ, Middleton MR, McGown G, Thorncroft M, Ranson M, Hersey P, McArthur G, Davis ID, Thomson D, Beith J, Haydon A, Kefford R, Lorigan P, Mortimer P, Sabharwal A, Hayward O, Margison GP. O(6)-methylguanine-DNA methyltransferase depletion and DNA damage in patients with melanoma treated with temozolomide alone or with lomeguatrib. Br J Cancer. 2009 Apr 21;100(8):1250-6. PubMed PMID: 19367283; PubMed Central PMCID: PMC2676560.

6: Kefford RF, Thomas NP, Corrie PG, Palmer C, Abdi E, Kotasek D, Beith J, Ranson M, Mortimer P, Watson AJ, Margison GP, Middleton MR. A phase I study of extended dosing with lomeguatrib with temozolomide in patients with advanced melanoma. Br J Cancer. 2009 Apr 21;100(8):1245-9. Epub 2009 Mar 31. PubMed PMID: 19367282; PubMed Central PMCID: PMC2676549.

7: Trinh VA. Current management of metastatic melanoma. Am J Health Syst Pharm. 2008 Dec 15;65(24 Suppl 9):S3-8. PubMed PMID: 19052264.

8: Khan OA, Ranson M, Michael M, Olver I, Levitt NC, Mortimer P, Watson AJ, Margison GP, Midgley R, Middleton MR. A phase II trial of lomeguatrib and temozolomide in metastatic colorectal cancer. Br J Cancer. 2008 May 20;98(10):1614-8. Epub 2008 May 13. Erratum in: Br J Cancer. 2009 Aug 4;101(3):550. PubMed PMID: 18475294; PubMed Central PMCID: PMC2391129.

9: Khan O, Middleton MR. The therapeutic potential of O6-alkylguanine DNA alkyltransferase inhibitors. Expert Opin Investig Drugs. 2007 Oct;16(10):1573-84. Review. PubMed PMID: 17922622.

10: Marchesi F, Turriziani M, Tortorelli G, Avvisati G, Torino F, De Vecchis L. Triazene compounds: mechanism of action and related DNA repair systems. Pharmacol Res. 2007 Oct;56(4):275-87. Epub 2007 Aug 9. Review. PubMed PMID: 17897837.

11: Ranson M, Hersey P, Thompson D, Beith J, McArthur GA, Haydon A, Davis ID, Kefford RF, Mortimer P, Harris PA, Baka S, Seebaran A, Sabharwal A, Watson AJ, Margison GP, Middleton MR. Randomized trial of the combination of lomeguatrib and temozolomide compared with temozolomide alone in chemotherapy naive patients with metastatic cutaneous melanoma. J Clin Oncol. 2007 Jun 20;25(18):2540-5. PubMed PMID: 17577032.

12: Caporaso P, Turriziani M, Venditti A, Marchesi F, Buccisano F, Tirindelli MC, Alvino E, Garbin A, Tortorelli G, Toppo L, Bonmassar E, D'Atri S, Amadori S. Novel role of triazenes in haematological malignancies: pilot study of Temozolomide, Lomeguatrib and IL-2 in the chemo-immunotherapy of acute leukaemia. DNA Repair (Amst). 2007 Aug 1;6(8):1179-86. Epub 2007 May 17. PubMed PMID: 17500047.

13: McMurry TB. MGMT inhibitors--The Trinity College-Paterson Institute experience, a chemist's perception. DNA Repair (Amst). 2007 Aug 1;6(8):1161-9. Epub 2007 May 7. PubMed PMID: 17485250.

14: Ranson M, Middleton MR, Bridgewater J, Lee SM, Dawson M, Jowle D, Halbert G, Waller S, McGrath H, Gumbrell L, McElhinney RS, Donnelly D, McMurry TB, Margison GP. 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. 2006 Mar 1;12(5):1577-84. PubMed PMID: 16533784.

15: Clemons M, Kelly J, Watson AJ, Howell A, McElhinney RS, McMurry TB, Margison GP. O6-(4-bromothenyl)guanine reverses temozolomide resistance in human breast tumour MCF-7 cells and xenografts. Br J Cancer. 2005 Nov 14;93(10):1152-6. PubMed PMID: 16278661; PubMed Central PMCID: PMC2361498.

16: Barvaux VA, Lorigan P, Ranson M, Gillum AM, McElhinney RS, McMurry TB, Margison GP. 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. 2004 Oct;3(10):1215-20. PubMed PMID: 15486188.