The potential for new and resilient anti-cancer drugs based upon minor groove binders for DNA A prospective view based on research at the University of Strathclyde.
Main Article Content
Abstract
Anti-infective and anticancer drugs share the serious problem that over time resistance develops to their effects leading to clinical obsolescence. Research at the University of Strathclyde has discovered a platform of anti-infective drugs based upon minor groove binders for DNA that have exceptional resilience to the development of resistance in their target organisms (bacteria, fungi, and parasites). This property is associated with the fact that the Strathclyde minor groove binders (S-MGBs) act at more than one discrete molecular target. One of the compounds has successfully completed a phase IIa clinical trial for the treatment of Clostridioides difficile infections. Several other compounds have shown activity against a number of cancer cell lines in vitro with indications of in vivo activity in a mouse model of lung cancer. This paper places these discoveries in the context of previous studies of minor groove binders as anticancer agents and considers whether the benefits of multitargeting successfully demonstrated in anti-infective applications can be translated to anticancer applications.
Article Details
How to Cite
SCOTT, Fraser J.; SUCKLING, Colin J..
The potential for new and resilient anti-cancer drugs based upon minor groove binders for DNA.
Medical Research Archives, [S.l.], v. 9, n. 11, nov. 2021.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2592>. Date accessed: 22 dec. 2024.
doi: https://doi.org/10.18103/mra.v9i11.2592.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Mansoori B, Mohammadi A, Davudian S, Shirjang S, Baradaran B. The Different mechanisms of cancer drug resistance: a brief review. Adv Pharm Bull. 2017; 7(3):339-348. doi: 10.15171/apb.2017.041
2. OECD (2018), Stemming the Superbug Tide: Just A Few Dollars More, OECD Publishing, Paris. doi.org/10.1787/9789264307599-en
3. Suckling CJ, Murphy JA, Khalaf AI, Zhou S-Z, Lizos LD, van Nhien AN, Morris BJ, Pratt JA, McVie A, Yasumatsu Y, Harvey AL, Young LC, McCraw C. Dual M4 agonists / 5HT7 antagonists with potential as antischizophrenic drugs – serominic compounds. Bioorg Med Chem Letters. 2007;17:2649-2655. doi:10.1016/j.bmcl.2007.01.093
4. Luan Y, Li J, Bernatchez JA, Li R. Kinase and Histone Deacetylase Hybrid Inhibitors for Cancer Therapy. J Med Chem. 2019;62: 3171−3183. DOI: 10.1021/acs.jmedchem.8b00189
5. Skok Ž, Zidar N, Kikelj D, Ilaš J. Dual Inhibitors of Human DNA Topoisomerase II and Other Cancer-Related Targets. J Med Chem. 2020, 63, 884−90. doi:10.1021/acs.jmedchem.9b00726
6. Muhsin M, Gricks C, Kirkpatrick P. Pemetrexed disodium. Nature Rev Drug Discov 2004;3:825–826. doi.org/10.1038/nrd1528
7. Lin A, Giuliano CJ, Palladino A, John KM, Abramowicz C, Yuan ML, Erin L. Sausville EL, Lukow DA, Liu L, Chait AR, Galluzzo ZC, Tucker C, Sheltzer JM. Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials. Science Translational Medicine. 2019 11(509):eaaw8412. DOI: 10.1126/scitranslmed.aaw8412
8. Chung EY, Mai Y, Shah UA, Wei Y, Ishida E, Kataoka K, Ren X, Pradhan K, Bartholdy B, Wei X, Zou Y, Zhang J, Ogawa S, Steidl U, Zang X, Verma A, Janakiram M, Ye BH. Clin Cancer Res. 2019;25: 3589-3601; DOI: 10.1158/1078-0432.CCR-18-3033
9. Anthony NG, Baiget J, Berretta G, Boyd M, Breen D, Gamble C, Gray AI, Harvey AL, Hatsiiemeria S, Ho KH, Huggan JK, Lang S, Llona-Minguez S, McIntosh K, Paul A, Plevin RJ, Robertson MN, Scott R, Suckling CJ, Sutcliffe O, Edwards J, Luo J, Young LC, McKay SP. Inhibitory kappa B kinase α (IKKα) inhibitors that recapitulate their selectivity in cells against isoform-related biomarkers. J Med Chem. 2017;60:7033-7066. doi; 10.102/acs.jmedchem.7b00484.
10. Smith JA, Bifulco G, Case DA, Boger DL, Gomez-Paloma L, Chazin WJ. The Structural basis for in situ activation of DNA alkylation by duocarmycin SA. J Mol Biol. 2000;300: 1195-1204. doi:10.1006/jmbi.2000.3887
11. Yao H-P, Zhao H, Hudson R, Tong X-M, Wang M-H. Duocarmycin-based antibody–drug conjugates as an emerging biotherapeutic entity for targeted cancer therapy: pharmaceutical strategy and clinical progress. Drug Discovery Today 2021;1359-6446. doi.org/10.1016/j.drudis.2021.06.012
12. Hartley JA, Flynn MJ, Bingham JP, Corbett S, Reinert H, Tiberghien A, Masterson LA, Antonow D, Adams L, Chowdhury S, Williams DG, Mao S, Harper J, Havenith CEG, Zammarchi F, Chivers F, van Berkel PH, Howard PW. Pre-clinical pharmacology and mechanism of action of SG3199, the pyrrolobenzodiazepine (PBD) dimer warhead component of antibody-drug conjugate (ADC) payload, tesirine. Scientific Reports. 2018;8:10479. doi:10.1038/s41598-018-28533-4
13. Rettig M, Langel W, Kamal A, Weisz K. NMR structural studies on the covalent DNA binding of a pyrrolobenzodiazepine–naphthalimide conjugate. Org Biomol Chem. 2010;8: 3179–3187. doi: 10.1039/c001893g
14. Larsen AK, Galmarini CM, D’Incalci M. Unique features of trabectedin mechanism of action. Cancer Chemother Pharmacol. 2016;77:663–671. DOI 10.1007/s00280-015-2918-1
15. Cozzi P. Recent outcome in the field of distamycin-derived minor groove binders. Il Farmaco 2000;55:168–173. doi:10.1016/s0014-827x(00)00013-6
16. Lee DY, Staddon AP, Shabason JE, Sebro R. Phase I and phase II clinical trials in sarcoma: implications for drug discovery and development. Cancer Medicine. 2019;8:585–592. doi:10.1002/cam4.1958
17. https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-comparing-brostallicin-with-doxorubicin-for-advanced-soft-tissue-sarcoma - brostacillin
18. Scott FJ, Nichol RJO, Khalaf AI, Giordani F, Gillingwater K, Ramu S, Elliott A, Zuegg J, Duffy P, Rosslee M-J, Hlaka L, Kumar S, Ozturk M, Brombacher F, Barrett MP, Guler R, Suckling CJ. An evaluation of Minor Groove Binders as anti-fungal and anti-mycobacterial therapeutics. Eur J Med Chem. 2017;136:561-572. doi.org/10.1016/j.ejmech.2017.05.039
19. Hlaka L, Rosslee M-J, Ozturk M, Santosh K, Parihar S, Brombacher F, Khalaf AI, Carter KC, Scott FJ, Suckling CJ, GulerR . Evaluation of Minor Groove Binders (MGBs) as novel anti-mycobacterial agents, and the effect of using non-ionic surfactant vesicles as a delivery system to improve their efficacy. J Antimicrob Chemother. 2017;72:3334-3341. doi:10.1093/jac/dkx326
20. Unpublished results, manuscript submitted.
21. Nichol RJO, Zhao C, Khalaf AI, May J, Suckling CJ, Scott FJ, Bromley M, MGBs: novel broad-spectrum antifungal agents. 2nd SCI / RSC Symposium on Antimicrobial Drug Discovery, 2018, London, England, 12th and 13th November 2018.
22. Giordani F, Khalaf AI, Gillingwater K, Munday J, de Koning H, Suckling CJ, Barrett MP, Scott FJ, Novel Minor Groove Binders cure animal African trypanosomiasis in an in vivo mouse model. J Med Chem. 2019;62:3021−3035, doi: 10.1021/acs.jmedchem.8b01847
23. Scott FJ, Khalaf AI, Duffy S, Avery VM, Suckling CJ. Selective anti-malarial minor groove binders. Bioorg Med Chem Letters. 2016;26:3326-3329. doi: 10.1016/j.bmcl.2016.05.039
24. MGB Biopharma. https://www.mgb-biopharma.com/mgb-biopharma-announces-successful-outcome-from-phase-ii-clinical-study-with-mgb-bp-3-a-potential-new-gold-standard-first-line-treatment-for-clostridium-difficile-infection-cdi/.
25. Kerr L, Browning DF, Lemonidis K, Salih T, Hunter IS, Suckling CJ, Tucker NP, Novel antibiotic mode of action by repression of promoter isomerization. BioRxiV 2020, doi: 10.1101/2020.12.31.424950
26. Kiakos K, Pett L, Satam V, Patil P, Hochhauser D, Lee M, Hartley JA. Nuclear localization and gene expression modulation by a fluorescent sequence-selective p-anisyl-benzimidazolecarboxamido imidazole-pyrrole polyamide. Chem Biol. 2015;22(7):862–875. doi:10.1016/j.chembiol/2015.06.005
27. Kiakos K, Satam S, Patil PC, Sweers J, Bowerman M, Tzou S, Olsen K, Lee M, Schaschl H, Keppler BK, Hochhauser D, Lee M, Hartley JA, Pett L. Effects of N-terminus modified Hx-amides on DNA binding affinity, sequence specificity, cellular uptake, and gene expression. Bioorg Med Chem Lett. 2021;47:128158. doi.org/10.1016/j.bmcl.2021.128158
28. Anthony NG, Johnston BF, Khalaf AI, MacKay SP, Parkinson JA, Suckling CJ, Waigh RD. A Short lexitropsin that recognizes the DNA minor groove at 5-ACTAGT-3: Understanding the role of isopropyl-thiazole J Am Chem Soc. 2004;126:11338-11349. doi:10.1021/ja030658n
29. Nichol R, Khalaf A, Sooda K, Hussain O, Griffiths H, Phillips RM, Javid F, Suckling CJ, Allison SS, Scott FJ. Selective in vitro anti-cancer activity of nonalkylating minor groove binders. Med Chem Commun. 2019;10:1620-1634. doi: 10.1039/c9md00268e
30. Scott FJ, Puig-Sellart M, Khalaf AI, Henderson CJ, Westrop G, Watson DG, Carter K, Grant HM, Suckling CJ. An evaluation of minor groove binders as anti-lung cancer therapeutics, Bioorg Med Chem Letters. 2016;26:3478-3486. doi: 10.1016/j.bmcl.2016.06.40
2. OECD (2018), Stemming the Superbug Tide: Just A Few Dollars More, OECD Publishing, Paris. doi.org/10.1787/9789264307599-en
3. Suckling CJ, Murphy JA, Khalaf AI, Zhou S-Z, Lizos LD, van Nhien AN, Morris BJ, Pratt JA, McVie A, Yasumatsu Y, Harvey AL, Young LC, McCraw C. Dual M4 agonists / 5HT7 antagonists with potential as antischizophrenic drugs – serominic compounds. Bioorg Med Chem Letters. 2007;17:2649-2655. doi:10.1016/j.bmcl.2007.01.093
4. Luan Y, Li J, Bernatchez JA, Li R. Kinase and Histone Deacetylase Hybrid Inhibitors for Cancer Therapy. J Med Chem. 2019;62: 3171−3183. DOI: 10.1021/acs.jmedchem.8b00189
5. Skok Ž, Zidar N, Kikelj D, Ilaš J. Dual Inhibitors of Human DNA Topoisomerase II and Other Cancer-Related Targets. J Med Chem. 2020, 63, 884−90. doi:10.1021/acs.jmedchem.9b00726
6. Muhsin M, Gricks C, Kirkpatrick P. Pemetrexed disodium. Nature Rev Drug Discov 2004;3:825–826. doi.org/10.1038/nrd1528
7. Lin A, Giuliano CJ, Palladino A, John KM, Abramowicz C, Yuan ML, Erin L. Sausville EL, Lukow DA, Liu L, Chait AR, Galluzzo ZC, Tucker C, Sheltzer JM. Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials. Science Translational Medicine. 2019 11(509):eaaw8412. DOI: 10.1126/scitranslmed.aaw8412
8. Chung EY, Mai Y, Shah UA, Wei Y, Ishida E, Kataoka K, Ren X, Pradhan K, Bartholdy B, Wei X, Zou Y, Zhang J, Ogawa S, Steidl U, Zang X, Verma A, Janakiram M, Ye BH. Clin Cancer Res. 2019;25: 3589-3601; DOI: 10.1158/1078-0432.CCR-18-3033
9. Anthony NG, Baiget J, Berretta G, Boyd M, Breen D, Gamble C, Gray AI, Harvey AL, Hatsiiemeria S, Ho KH, Huggan JK, Lang S, Llona-Minguez S, McIntosh K, Paul A, Plevin RJ, Robertson MN, Scott R, Suckling CJ, Sutcliffe O, Edwards J, Luo J, Young LC, McKay SP. Inhibitory kappa B kinase α (IKKα) inhibitors that recapitulate their selectivity in cells against isoform-related biomarkers. J Med Chem. 2017;60:7033-7066. doi; 10.102/acs.jmedchem.7b00484.
10. Smith JA, Bifulco G, Case DA, Boger DL, Gomez-Paloma L, Chazin WJ. The Structural basis for in situ activation of DNA alkylation by duocarmycin SA. J Mol Biol. 2000;300: 1195-1204. doi:10.1006/jmbi.2000.3887
11. Yao H-P, Zhao H, Hudson R, Tong X-M, Wang M-H. Duocarmycin-based antibody–drug conjugates as an emerging biotherapeutic entity for targeted cancer therapy: pharmaceutical strategy and clinical progress. Drug Discovery Today 2021;1359-6446. doi.org/10.1016/j.drudis.2021.06.012
12. Hartley JA, Flynn MJ, Bingham JP, Corbett S, Reinert H, Tiberghien A, Masterson LA, Antonow D, Adams L, Chowdhury S, Williams DG, Mao S, Harper J, Havenith CEG, Zammarchi F, Chivers F, van Berkel PH, Howard PW. Pre-clinical pharmacology and mechanism of action of SG3199, the pyrrolobenzodiazepine (PBD) dimer warhead component of antibody-drug conjugate (ADC) payload, tesirine. Scientific Reports. 2018;8:10479. doi:10.1038/s41598-018-28533-4
13. Rettig M, Langel W, Kamal A, Weisz K. NMR structural studies on the covalent DNA binding of a pyrrolobenzodiazepine–naphthalimide conjugate. Org Biomol Chem. 2010;8: 3179–3187. doi: 10.1039/c001893g
14. Larsen AK, Galmarini CM, D’Incalci M. Unique features of trabectedin mechanism of action. Cancer Chemother Pharmacol. 2016;77:663–671. DOI 10.1007/s00280-015-2918-1
15. Cozzi P. Recent outcome in the field of distamycin-derived minor groove binders. Il Farmaco 2000;55:168–173. doi:10.1016/s0014-827x(00)00013-6
16. Lee DY, Staddon AP, Shabason JE, Sebro R. Phase I and phase II clinical trials in sarcoma: implications for drug discovery and development. Cancer Medicine. 2019;8:585–592. doi:10.1002/cam4.1958
17. https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-comparing-brostallicin-with-doxorubicin-for-advanced-soft-tissue-sarcoma - brostacillin
18. Scott FJ, Nichol RJO, Khalaf AI, Giordani F, Gillingwater K, Ramu S, Elliott A, Zuegg J, Duffy P, Rosslee M-J, Hlaka L, Kumar S, Ozturk M, Brombacher F, Barrett MP, Guler R, Suckling CJ. An evaluation of Minor Groove Binders as anti-fungal and anti-mycobacterial therapeutics. Eur J Med Chem. 2017;136:561-572. doi.org/10.1016/j.ejmech.2017.05.039
19. Hlaka L, Rosslee M-J, Ozturk M, Santosh K, Parihar S, Brombacher F, Khalaf AI, Carter KC, Scott FJ, Suckling CJ, GulerR . Evaluation of Minor Groove Binders (MGBs) as novel anti-mycobacterial agents, and the effect of using non-ionic surfactant vesicles as a delivery system to improve their efficacy. J Antimicrob Chemother. 2017;72:3334-3341. doi:10.1093/jac/dkx326
20. Unpublished results, manuscript submitted.
21. Nichol RJO, Zhao C, Khalaf AI, May J, Suckling CJ, Scott FJ, Bromley M, MGBs: novel broad-spectrum antifungal agents. 2nd SCI / RSC Symposium on Antimicrobial Drug Discovery, 2018, London, England, 12th and 13th November 2018.
22. Giordani F, Khalaf AI, Gillingwater K, Munday J, de Koning H, Suckling CJ, Barrett MP, Scott FJ, Novel Minor Groove Binders cure animal African trypanosomiasis in an in vivo mouse model. J Med Chem. 2019;62:3021−3035, doi: 10.1021/acs.jmedchem.8b01847
23. Scott FJ, Khalaf AI, Duffy S, Avery VM, Suckling CJ. Selective anti-malarial minor groove binders. Bioorg Med Chem Letters. 2016;26:3326-3329. doi: 10.1016/j.bmcl.2016.05.039
24. MGB Biopharma. https://www.mgb-biopharma.com/mgb-biopharma-announces-successful-outcome-from-phase-ii-clinical-study-with-mgb-bp-3-a-potential-new-gold-standard-first-line-treatment-for-clostridium-difficile-infection-cdi/.
25. Kerr L, Browning DF, Lemonidis K, Salih T, Hunter IS, Suckling CJ, Tucker NP, Novel antibiotic mode of action by repression of promoter isomerization. BioRxiV 2020, doi: 10.1101/2020.12.31.424950
26. Kiakos K, Pett L, Satam V, Patil P, Hochhauser D, Lee M, Hartley JA. Nuclear localization and gene expression modulation by a fluorescent sequence-selective p-anisyl-benzimidazolecarboxamido imidazole-pyrrole polyamide. Chem Biol. 2015;22(7):862–875. doi:10.1016/j.chembiol/2015.06.005
27. Kiakos K, Satam S, Patil PC, Sweers J, Bowerman M, Tzou S, Olsen K, Lee M, Schaschl H, Keppler BK, Hochhauser D, Lee M, Hartley JA, Pett L. Effects of N-terminus modified Hx-amides on DNA binding affinity, sequence specificity, cellular uptake, and gene expression. Bioorg Med Chem Lett. 2021;47:128158. doi.org/10.1016/j.bmcl.2021.128158
28. Anthony NG, Johnston BF, Khalaf AI, MacKay SP, Parkinson JA, Suckling CJ, Waigh RD. A Short lexitropsin that recognizes the DNA minor groove at 5-ACTAGT-3: Understanding the role of isopropyl-thiazole J Am Chem Soc. 2004;126:11338-11349. doi:10.1021/ja030658n
29. Nichol R, Khalaf A, Sooda K, Hussain O, Griffiths H, Phillips RM, Javid F, Suckling CJ, Allison SS, Scott FJ. Selective in vitro anti-cancer activity of nonalkylating minor groove binders. Med Chem Commun. 2019;10:1620-1634. doi: 10.1039/c9md00268e
30. Scott FJ, Puig-Sellart M, Khalaf AI, Henderson CJ, Westrop G, Watson DG, Carter K, Grant HM, Suckling CJ. An evaluation of minor groove binders as anti-lung cancer therapeutics, Bioorg Med Chem Letters. 2016;26:3478-3486. doi: 10.1016/j.bmcl.2016.06.40