Lomeguatrib
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MedKoo CAT#: 201750

CAS#: 192441-08-0

Description: Lomeguatrib, also known as PaTrin-2, 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 can be used with temozolomide (TMZ) for GBM treatment.

Chemical Structure

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Lomeguatrib
CAS# 192441-08-0
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 201750
Name: Lomeguatrib
CAS#: 192441-08-0
Chemical Formula: C10H8BrN5OS
Exact Mass: 324.96
Molecular Weight: 326.170
Elemental Analysis: C, 36.82; H, 2.47; Br, 24.50; N, 21.47; O, 4.91; S, 9.83

Price and Availability

Size Price Availability Quantity
10mg USD 90 Ready to ship
25mg USD 150 Ready to ship
50mg USD 250 Ready to ship
100mg USD 450 Ready to ship
200mg USD 800 Ready to ship
500mg USD 1650 Ready to ship
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Synonym: PaTrin 2; PaTrin2; PaTrin-2; Lomeguatrib.

IUPAC/Chemical Name: 2-Amino-6-[(4-bromo-2-thienyl)methoxy]-9H-purine

InChi Key: JUJPKFNFCWJBCX-UHFFFAOYSA-N

InChi Code: InChI=1S/C10H8BrN5OS/c11-5-1-6(18-3-5)2-17-9-7-8(14-4-13-7)15-10(12)16-9/h1,3-4H,2H2,(H3,12,13,14,15,16)

SMILES Code: BrC1=CSC(COC2=C3N=CNC3=NC(N)=N2)=C1

Appearance: Off-white to grey solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

More Info:         

Biological target: Lomeguatrib is a O6-methylguanine-DNA methyltransferase (MGMT) inhibitor, with IC50s of 9 nM in cell-free assay and ∼6 nM in MCF-7 cells.
In vitro activity: To determine whether targeting DUB3 could be an alternative choice for indirectly mitigating MCL1 activity, several SMIs were screened and expression level of DUB3 was detected. Both the results from qRT-PCR screening and further immunoblotting validation revealed that PaTrin-2 was the most effective SMI in repressing DUB3 expression (SI Appendix, Fig. S6 A and B). PaTrin2 treatment reduced the mRNA and protein levels of DUB3 in a dose-dependent manner, whereas only the protein expression level of MCL1 was decreased in response to treatment (Fig. 4A and SI Appendix, Fig. S6 C and D). PaTrin-2 is a potent and minimally toxic MGMT inhibitor that acts as a pseudosubstrate of MGMT. To verify that the PaTrin-2-induced suppression of DUB3 was mediated by the inhibition of MGMT, MGMT was knocked down in OVCAR3 and OVCA433 cells and found that the MGMT depletion significantly reduced the protein levels of both DUB3 and MCL1, but only the mRNA expression of DUB3 (Fig. 4B and SI Appendix, Fig. S6 E and F). The ubiquitin assay showed that MCL1 ubiquitination was increased after the PaTrin-2 treatment (SI Appendix, Fig. S6G), further confirming that PaTrin-2 promotes the ubiquitination and degradation of MCL1 by suppressing DUB3 transcription. To investigate the potential therapeutic effect of PaTrin-2 on chemoresistance in ovarian cancer, administered PaTrin-2 was administered to OVCAR3 and OVCA433 cells expressing high levels of MGMT-DUB3-MCL1 and A2780 and ES-2 cells expressing low levels of MGMT-DUB3-MCL1. The PaTrin-2 treatment significantly inhibited proliferation of ovarian cancer cells expressing high levels of MGMT-DUB3-MCL1. Reference: Proc Natl Acad Sci U S A. 2019 Feb 19; 116(8): 2961–2966. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386650/
In vivo activity: It was considered worthwhile to examine the extent to which PaTrin-2 could inactivate MGMT and increase sensitivity to temozolomide in a human breast tumour model as a prerequisite for any potential clinical trial in breast cancer. The results show that PaTrin-2 is also a potent inactivator of MGMT in MCF-7 cells both in culture and in xenografts in vivo. Tumour MGMT depletion by PaTrin-2 was as extensive as was reported with O6-BeG in other tumour types (see Dolan and Pegg, 1997). It also showed that MGMT was inactivated in all host tissues with complete inactivation in kidney and extensive inactivation in other tissues. This collateral depletion again raises the concern about the potentiation of toxicity in healthy tissues following PaTrin-2/alkylating agent combinations. The MGMT inactivation by PaTrin-2 in MCF-7 cells resulted in marked sensitisation to temozolomide growth inhibition. Following implantation into immune deficient mice, PaTrin-2 alone had, as anticipated, no effect on tumour growth rates. However, PaTrin-2 overcame the resistance to temozolomide producing highly significant tumour growth delays, but without increasing toxicity as judged by animal weights. Thus, the therapeutic index of temozolomide is increased by PaTrin-2 in this animal model. Given the results of the xenograft studies with melanoma, and now breast cancer, it seems reasonable to speculate that the greatest benefit from PaTrin-2-mediated inactivation of MGMT might be seen in tumours with the highest levels of MGMT expression and inherent resistance to temozolomide. Reference: Br J Cancer. 2005 Nov 14; 93(10): 1152–1156. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361498/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 51.2 156.99

Preparing Stock Solutions

The following data is based on the product molecular weight 326.17 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. 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. doi: 10.1038/sj.bjc.6602833. PMID: 16278661; PMCID: PMC2361498. 2. Wu X, Luo Q, Zhao P, Chang W, Wang Y, Shu T, Ding F, Li B, Liu Z. MGMT-activated DUB3 stabilizes MCL1 and drives chemoresistance in ovarian cancer. Proc Natl Acad Sci U S A. 2019 Feb 19;116(8):2961-2966. doi: 10.1073/pnas.1814742116. Epub 2019 Feb 4. PMID: 30718431; PMCID: PMC6386650.
In vitro protocol: 1. 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. doi: 10.1038/sj.bjc.6602833. PMID: 16278661; PMCID: PMC2361498. 2. Wu X, Luo Q, Zhao P, Chang W, Wang Y, Shu T, Ding F, Li B, Liu Z. MGMT-activated DUB3 stabilizes MCL1 and drives chemoresistance in ovarian cancer. Proc Natl Acad Sci U S A. 2019 Feb 19;116(8):2961-2966. doi: 10.1073/pnas.1814742116. Epub 2019 Feb 4. PMID: 30718431; PMCID: PMC6386650.
In vivo protocol: 1. 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. doi: 10.1038/sj.bjc.6602833. PMID: 16278661; PMCID: PMC2361498.

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1: Ugur HC, Taspinar M, Ilgaz S, Sert F, Canpinar H, Rey JA, Castresana JS, Sunguroglu A. Chemotherapeutic resistance in anaplastic astrocytoma cell lines treated with a temozolomide-lomeguatrib combination. Mol Biol Rep. 2014 Feb;41(2):697-703. doi: 10.1007/s11033-013-2908-5. Epub 2013 Dec 25. PubMed PMID: 24368590.

2: Taspinar M, Ilgaz S, Ozdemir M, Ozkan T, Oztuna D, Canpinar H, Rey JA, Sunguroğlu A, Castresana JS, Ugur HC. Effect of lomeguatrib-temozolomide combination on MGMT promoter methylation and expression in primary glioblastoma tumor cells. Tumour Biol. 2013 Jun;34(3):1935-47. doi: 10.1007/s13277-013-0738-7. Epub 2013 Mar 22. PubMed PMID: 23519841.

3: 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 Sep 6;105(6):773-7. doi: 10.1038/bjc.2011.285. Epub 2011 Aug 2. PubMed PMID: 21811257; PubMed Central PMCID: PMC3171007.

4: 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. doi: 10.1158/1078-0432.CCR-09-1389. Epub 2010 Jan 12. PubMed PMID: 20068091; PubMed Central PMCID: PMC2807621.

5: 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. doi: 10.1007/s00280-009-1225-0. Epub 2009 Dec 29. PubMed PMID: 20039040.

6: 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. doi: 10.1038/sj.bjc.6605015. PubMed PMID: 19367283; PubMed Central PMCID: PMC2676560.

7: 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. doi: 10.1038/sj.bjc.6605016. Epub 2009 Mar 31. PubMed PMID: 19367282; PubMed Central PMCID: PMC2676549.

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. doi: 10.1038/sj.bjc.6604366. Epub 2008 May 13. Erratum in: Br J Cancer. 2009 Aug 4;101(3):550. PubMed PMID: 18475294; PubMed Central PMCID: PMC2391129.

9: 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.

10: 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.

11: 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.