[[File:ONX-0801_structure.png|thumb|right|Chemical structure of ONX-0801]]
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'''ONX-0801''' is a novel [[antifolate]] drug that has been investigated for its potential use in the treatment of [[cancer]]. It is designed to target the [[folate receptor alpha]] (FR_), which is overexpressed in certain types of cancer cells, including [[ovarian cancer]] and [[non-small cell lung cancer]].
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=== Mechanism of Action ===
| CAS_number = 501332-69-0
ONX-0801 functions as a targeted antifolate agent. It inhibits the enzyme [[thymidylate synthase]], which is crucial for [[DNA synthesis]] and [[cell division]]. By selectively binding to the folate receptor alpha, ONX-0801 is preferentially taken up by cancer cells that overexpress this receptor, thereby minimizing effects on normal cells and reducing [[toxicity]].
ONX-0801 has undergone [[clinical trials]] to evaluate its safety and efficacy. Early-phase trials have shown promising results, particularly in patients with FR_-positive tumors. The drug's ability to selectively target cancer cells offers a potential advantage over traditional [[chemotherapy]] agents, which often affect both cancerous and healthy cells.
'''ONX-0801''' ('''BGC 945''') is an experimental drug that has been developed to target [[ovarian cancer]].<ref>{{Cite web|url=http://www.icr.ac.uk/news-archive/ovarian-cancer-drug-delivers-very-promising-results-in-early-trial|title=Ovarian cancer drug delivers ‘very promising’ results in early trial|last=|first=|date=3 June 2017|website=The Institute of Cancer Research, London|archive-url=|archive-date=|dead-url=|access-date=2017-06-03}}</ref> It is a [[folate receptor alpha]] mediated [[thymidylate synthase inhibitor]].<ref>{{Cite news|url=http://www.hra.nhs.uk/news/research-summaries/a-phase-i-trial-of-onx-0801/|title=A Phase I trial of ONX-0801|last=|first=|date=19 July 2013|work=Health Research Authority|access-date=2017-06-03|archive-url=|archive-date=|dead-url=|language=en-US}}</ref><ref>Jarmula A. Antifolate inhibitors of thymidylate synthase as anticancer drugs. ''Mini Reviews in Medicinal Chemistry'' 10.13 (2010): 1211-1222. {{PMID|20854257}}</ref>
=== Potential Benefits ===
The targeted nature of ONX-0801 may lead to fewer side effects compared to conventional chemotherapy. This specificity could result in improved [[quality of life]] for patients undergoing treatment. Additionally, the drug's mechanism of action provides a new therapeutic option for patients with tumors that are resistant to other forms of treatment.
ONX-0801 was originally developed by [[BTG plc|BTG]] and the [[Institute of Cancer Research]] in the UK, and subsequently licensed to [[Onyx Pharmaceuticals]] for clinical development. It is designed to selectively target tumour tissues of certain kinds of cancer.<ref>Gibbs DD, Theti DS, Wood N, Green M, Raynaud F, Valenti M, Forster MD, Mitchell F, Bavetsias V, Henderson E, Jackman AL. BGC 945, a novel tumor-selective thymidylate synthase inhibitor targeted to alpha-folate receptor-overexpressing tumors. ''Cancer Res''. 2005 Dec 15;65(24):11721-8. {{PMID|16357184}}</ref> It is poorly absorbed into most cells, but is actively transported by folate receptor alpha (FRα), which is usually only expressed at low levels in the [[apical membrane]] of some specialised tissues, but is expressed at much higher levels in some subtypes of [[ovarian cancer]]. This causes the drug to accumulate selectively in tumour tissues, while healthy tissues are only exposed to a much lower concentration.<ref>Ng C, et al. Efficacy and tolerability of the thymidylate synthase (TS) inhibitor, BGC 945 is mediated through its selective uptake via the α-folate receptor (α-FR) in IGROV-1 human tumor xenografts. ''Cancer Res'' May 1, 2008 (68) (9 Supplement): 3289.</ref><ref>Ng CHM, Jackman AL. Potential for α-Folate Receptor-Targeted Treatment for Ovarian Cancer. ''Emerging Therapeutic Targets in Ovarian Cancer''. Springer New York, 2011. 245-258.</ref><ref>Tochowicz A, Dalziel S, Eidam O, O'Connell JD 3rd, Griner S, Finer-Moore JS, Stroud RM. Development and binding mode assessment of N-[4-[2-propyn-1-yl[(6S)-4,6,7,8-tetrahydro-2-(hydroxymethyl)-4-oxo-3H-cyclopenta[g]quinazolin-6-yl]amino]benzoyl]-l-γ-glutamyl-D-glutamic acid (BGC 945), a novel thymidylate synthase inhibitor that targets tumor cells. ''J Med Chem''. 2013 Jul 11;56(13):5446-55. doi: 10.1021/jm400490e {{PMID|23710599}}</ref>
=== Challenges and Future Directions ===
Despite its potential, ONX-0801 faces challenges in its development. These include the need for reliable biomarkers to identify patients who would benefit most from the treatment and the management of any unforeseen side effects. Ongoing research is focused on optimizing dosing regimens and exploring combination therapies with other anticancer agents.
In 2017, it received press coverage following the successful completion of a [[Phase I clinical trial]].<ref>{{Cite news|url=https://www.bbc.co.uk/news/health-40097274|title=Drug shrinks ovarian tumours in early trial|last=Warry|first=Richard|date=2017-06-03|work=BBC News|access-date=2017-06-03|language=en-GB}}</ref><ref>{{Cite news|url=https://www.independent.co.uk/news/health/ovarian-cancer-treatment-advanced-latest-tumours-breakthrough-a7769746.html|title=Researchers hail biggest breakthrough in advanced ovarian cancer for a decade|date=2017-06-02|work=The Independent|access-date=2017-06-03|language=en-GB}}</ref><ref>[http://abstracts.asco.org/199/AbstView_199_182632.html Banerji U, et al. An investigator-initiated phase I study of ONX-0801, a first-in-class alpha folate receptor targeted, small molecule thymidylate synthase inhibitor in solid tumors. ''J Clin Oncol'' 35, 2017 (suppl; abstr 2503)]</ref>
ONX-0801 functions as a targeted antifolate agent. It inhibits the enzyme thymidylate synthase, which is crucial for DNA synthesis and cell division. By selectively binding to the folate receptor alpha, ONX-0801 is preferentially taken up by cancer cells that overexpress this receptor, thereby minimizing effects on normal cells and reducing toxicity.
ONX-0801 has undergone clinical trials to evaluate its safety and efficacy. Early-phase trials have shown promising results, particularly in patients with FR_-positive tumors. The drug's ability to selectively target cancer cells offers a potential advantage over traditional chemotherapy agents, which often affect both cancerous and healthy cells.
The targeted nature of ONX-0801 may lead to fewer side effects compared to conventional chemotherapy. This specificity could result in improved quality of life for patients undergoing treatment. Additionally, the drug's mechanism of action provides a new therapeutic option for patients with tumors that are resistant to other forms of treatment.
Despite its potential, ONX-0801 faces challenges in its development. These include the need for reliable biomarkers to identify patients who would benefit most from the treatment and the management of any unforeseen side effects. Ongoing research is focused on optimizing dosing regimens and exploring combination therapies with other anticancer agents.
