Barry V. L. Potter

Barry Victor Lloyd Potter (born 1953) MAE FMedSci is Professor of Medicinal & Biological Chemistry[1] at the University of Oxford, Wellcome Trust Senior Investigator and a Fellow of University College, Oxford.[2]

Barry V L Potter

DSc MAE FMedSci
Barry Potter at the University of Bath, UK
Born
Brighton, Sussex, UK
Awards
  • RSC Medal for Chemical Biology (2007)
  • RSC George and Christine Sosnovsky Medal in Cancer Therapy (2007/8)
  • GlaxoSmithKline International Achievement Award (2009)
  • RSC Malcolm Campbell Memorial Medal (2009)
  • RSC 2010 Interdisciplinary Medal (2010)
  • 2012 European Life Science Award
  • RSC-BMCS Lectureship (2015/16)
  • Tu Youyou Award for Natural Product and Medicinal Chemistry (2018)
  • Fellow of the Royal Society of Chemistry
  • Fellow of the Royal Society of Biology
  • Member Academia Europaea
  • Fellow of the Academy of Medical Sciences
Academic background
EducationHove County Grammar School
Alma mater
  • University of Oxford MA, DPhil, DSc
  • Worcester College
  • Wolfson College
  • University College
ThesisAn Investigation of Enzyme Mechanisms using Substrate Analogues
Doctoral advisorGordon Lowe FRS
Academic work
Institutions
  • University of Oxford
  • Max-Planck-Institut für experimentelle Medizin, Göttingen
  • University of Leicester
  • University of Bath
  • University of Oxford
Notable worksStereochemistry of Phosphoryl Transfer

Chemistry of Signal Transduction

Drug Design & Discovery, Irosustat, E2MATE, Steroid Sulfatase
Websitepharm.ox.ac.uk/team/barry-v-l-potter

Early life and education

Potter was born in Brighton, Sussex and attended Hove County Grammar School. He won an Open Exhibition scholarship to Worcester College, University of Oxford to study Chemistry and obtained a first class Bachelor of Arts degree (with a subsequent MA), also winning the Part II Thesis Prize in Organic Chemistry. He earned a Doctor of Philosophy degree[3] from Wolfson College, Oxford for work carried out in the Dyson Perrins Laboratory on the stereochemistry of enzyme-catalyzed phosphoryl transfer reactions under the supervision of Gordon Lowe FRS. He was subsequently awarded a DSc degree from the University of Oxford for his published work up to 1992 in “Studies in Biological Chemistry”.[4]

Career and research

Potter was a postdoctoral research associate first at Oxford and subsequently was funded by the Royal Society to work at the Max Planck Institute for Experimental Medicine in Göttingen, Federal Republic of Germany with Professor Fritz Eckstein in the nucleic acid and molecular biology fields and he later became a Wissenschaftlicher Mitarbeiter. He was lecturer in biological chemistry in the Department of Chemistry at the University of Leicester, a Lister Institute of Preventive Medicine Research Fellow and held the established chair of Medicinal Chemistry at University of Bath for over 20 years, initially as Lister Institute Research Professor, and is currently a visiting professor. He was visiting professor of medicinal and biological chemistry at the University of Oxford until 2015. His research, primarily employing synthetic organic chemistry, is highly interdisciplinary at the interfaces of Chemistry with Biology and with Medicine and encompasses medicinal and biological chemistry, chemical biology and drug design, discovery and development, especially for oncology and women's health.

He is particularly known for his enzyme mechanistic work on the sterochemistry of enzyme reactions that transfer phosphate groups eg kinases, phosphatases, polymerases, nucleases etc, pioneering application of synthetic chiral isotopomeric phosphates using both stable isotopes of 16O-oxygen in the [16O,17O,18O] - approach, also using the 18O-isotope in combination with sulphur in the [16O,18O, S] - approach and the [16O,18O] - approach for internucleotidic linkages; and the application of synthetic and biological chemistry techniques to cellular signalling through the study of the calcium-releasing second messengers inositol trisphosphate (IP3), cyclic adenosine 5'-diphosphate ribose (cADPR), nicotinic acid adenine diphosphate ribose 2'-phosphate (NAADP) and adenosine 5'-diphosphate ribose (ADPR) and also more widely in nucleotide and carbohydrate chemistry.

In his drug design and discovery work one of the "first-in-class" academically discovered clinical drug targets identified is steroid sulfatase (STS) [5] and the first potent inhibitor designed and synthesized by the Potter research group was the steroidal sulfamate EMATE.[6] Synthetic active-site-directed, irreversible, time-dependent steroidal and non-steroidal inactivators of the enzyme progressed to clinical trials [7] and were translated to the pharmaceutical industry. This work in collaboration with Michael J Reed lead to sulfamate-based drugs such as Irosustat (BN83495, STX64) [8][9][10] and E2MATE (PGL2001) that have completed many clinical trials in women's health, including for hormone replacement therapy and endometriosis,[11][12] post-menopausal ER+ hormone dependent breast cancer,[13][14][15][16][17] advanced/metastatic or recurrent estrogen receptor-positive endometrial cancer [18][19] and castration-resistant prostate cancer [20][21] and are still progressing clinically. E2MATE/PGL2001 was well tolerated and first clinical trials showed that local endometrial STS could be reduced by 91% by a single dose of only 4 mg/per week of the drug alone and 96% in combination with a progestin.[12] A Phase II, multicentre, randomised, two-arm, parallel group, double-blind, placebo controlled, clinical study was initiated.[11] Results are awaited. In randomised phase II trials using Irosustat vs the current standard of care (megestrol acetate) in recurrent/metastatic post-menopausal endometrial cancer patients results showed clinical activity and a good safety profile. Pharmacodynamic proof of concept for Irosustat was demonstrated in prostate cancer patients with suppression of the non-sulfated androgens testosterone, androstenediol and DHEA. The most recent IRIS [22] and IPET [23] breast cancer clinical trials [16][17] met their clinical endpoints; results were discussed [24][25] and clinical benefit demonstrated for Irosustat both as a monotherapy in early breast cancer and in combination with an aromatase inhibitor. Further trials are necessary.

Potter co-founded in 1997 the university spin-out company Sterix Limited [26] jointly between the University of Bath and Imperial College, London. Sterix Ltd pioneered inter alia the first human clinical trials of a steroid sulfatase inhibitor in breast cancer patients [13] and was acquired by the French Ipsen Group in 2004.[27]

Awards and honours

Potter was elected a Fellow of the Academy of Medical Sciences (FMedSci) in 2008.[28] The citation reads:

He has made wide-ranging contributions at the interface of Chemistry with both Biology and Medicine. In Chemical Biology he has elucidated the stereochemistry of numerous enzyme-catalysed phosphoryl and nucleotidyl transfer reactions using isotopically chiral substrates and DNA fragments. He has applied organic synthesis techniques in novel ways using carbohydrate, cyclitol and phosphorus chemistry to design modulators of cellular signal transduction processes that mobilize intracellular Ca2+ through second messengers. Of particular relevance to this Academy he has pioneered the novel aryl sulfamate pharmacophore in drug design. Unusually within an academic setting, he has brought compounds from initial academic concept to multiple clinical trials in women’s health. These have shown evidence of efficacy in humans, particularly in the anti-cancer field related to hormone-dependent breast cancer.

He was elected a Member (MAE) of the pan-European Academy of Science, Humanities & Letters the Academia Europaea in 2009.[29]

He has also won a number of academic and industrial awards and medals e.g.: Royal Society of Chemistry, 2007 UCB-Celltech Industrially Sponsored Award & Medal for Chemical Biology;[30] Royal Society of Chemistry, 2007/8 George and Christine Sosnovsky Award & Medal in Cancer Therapy;[31] 2009 GlaxoSmithKline International Achievement Award;[32] Royal Society of Chemistry, Biological & Medicinal Chemistry Section, 2009 Malcolm Campbell Memorial Prize & Medal (jointly);[33] Royal Society of Chemistry 2010 Interdisciplinary Prize & Medal;[34] 2012 European Life Science Award, Investigator of the Year;[35] Royal Society of Chemistry, Biological & Medicinal Chemistry Section, 2015/16 2nd RSC-BMCS Lectureship;[36] 2018 Tu Youyou Award for Natural Product and Medicinal Chemistry.[37]

References
  1. "Department of Pharmacology, University of Oxford".
  2. "Academics". University College Oxford.
  3. "An investigation of enzyme mechanisms using substrate analogues". Bodleian Library, Oxford. 1980.
  4. "Studies in Biological Chemistry". Bodleian Library, Oxford. 1992.
  5. Thomas, MP, Potter BVL (2015). "Discovery and Development of the Aryl O-Sulfamate Pharmacophore for Oncology and Women's Health". J. Med. Chem. 58 (19): 7634–58. doi:10.1021/acs.jmedchem.5b00386. PMC 5159624. PMID 25992880.
  6. Howarth, NM, Purohit A, Reed MJ, Potter BVL (1994). "Estrone sulfamates: potent inhibitors of estrone sulfatase with therapeutic potential". J. Med. Chem. 37 (2): 219–221. doi:10.1021/jm00028a002. PMID 8295207.
  7. Potter, BVL (2018). "Steroid sulphatase inhibition via aryl sulphamates: clinical progress, mechanism and future prospects". J. Mol. Endocrinol. 61 (2): T233-252. doi:10.1530/JME-18-0045. PMID 29618488.
  8. "Irosustat". NIH US National Library of Medicine, PubChem Open Chemistry Database.
  9. "Irosustat". ChemSpider.
  10. CHEMBL286738. "Irosustat". ChEMBL European Bioinformatics Institute [GB].
  11. "PGL2001 Proof of Concept Study in Symptomatic Endometriosis (AMBER)". NIH US National Library of Medicine ClinicalTrials.gov.
  12. Pohl, O, Bestel E, Gotteland JP (2014). "Synergistic effects of E2MATE and norethindrone acetate on steroid sulfatase inhibition: a randomized phase I proof-of-principle clinical study in women of reproductive age". Reprod. Sci. 21 (10): 1256–65. doi:10.1177/1933719114522526. PMID 24604234. S2CID 206805308 – via 1933719114522526.
  13. Stanway, S, Purohit A, Woo LWL, Sufi S, Vigushin D, Ward R, Wilson R, Stanczyk FZ, Dobbs N, Kulinskaya E, Elliott M, Potter BVL, Reed MJ, Coombes RC (2006). "Phase I study of STX64 (667 Coumate) in breast cancer patients: the first study of a steroid sulfatase inhibitor". Clin. Cancer Res. 12 (5): 1585–1592. doi:10.1158/1078-0432.CCR-05-1996. PMID 16533785.
  14. Coombes, RC, Cardoso F, Isambert N, Lesimple T, Soulié P, Peraire C, Fohanno V, Kornowska A, Ali T, Schmid P (2013). "A phase I dose escalation study to determine the optimal biological dose of irosustat, an oral steroid sulfatase inhibitor, in postmenopausal women with estrogen receptor-positive breast cancer". Breast Cancer Res. Treat. 140 (1): 73–82. doi:10.1007/s10549-013-2597-8. PMID 23797179. S2CID 20060727 – via s10549-013-2597-8_.
  15. "BN83495 Phase I in Post-menopausal Women". NIH US National Library of Medicine ClinicalTrials.gov.
  16. Palmieri, C, Stein RC, Liu X, Hudson E, Nicholas H, Sasano H, Guestini F, Holcombe C, Barrett S, Kenny L, Reed S, Lim A, Hayward L, Howell S, Coombes RC; IRIS trial participants (2017). "IRIS study: a phase II study of the steroid sulfatase inhibitor Irosustat when added to an aromatase inhibitor in ER-positive breast cancer patients". Breast Cancer Res. Treat. 165 (2): 343–353. doi:10.1007/s10549-017-4328-z. PMC 5543190. PMID 28612226 – via s10549-017-4328-z.
  17. Palmieri, C, Szydlo R, Miller M, Barker L, Patel NH, Sasano H, Barwick T, Tam H, Hadjiminas D, Lee J, Shaaban A, Nicholas H, Coombes RC, Kenny LM (2017). "IPET study: an FLT-PET window study to assess the activity of the steroid sulfatase inhibitor irosustat in early breast cancer". Breast Cancer Res. Treat. 166 (2): 527–539. doi:10.1007/s10549-017-4427-x. PMC 5668341. PMID 28795252 – via s10549-017-4427-x.
  18. "Study of Oral Steroid Sulphatase Inhibitor BN83495 Versus Megestrol Acetate (MA) in Women With Advanced or Recurrent Endometrial Cancer". NIH US National Library of Medicine ClinicalTrials.gov.
  19. Pautier, P, Vergote I, Joly F, Melichar B, Kutarska E, Hall G, Lisyanskaya A, Reed N, Oaknin A, Ostapenko V, Zvirbule Z, Chetaille E, Geniaux A, Shoaib M, Green JA (2017). "A Phase 2, Randomized, Open-Label Study of Irosustat Versus Megestrol Acetate in Advanced Endometrial Cancer". Int. J. Gynecol. Cancer. 27 (2): 258–266. doi:10.1097/igc.0000000000000862. PMID 27870712. S2CID 3430946 – via IGC.0000000000000862.
  20. "BN83495 in Prostate Cancer (STX64PC)". NIH US National Library of Medicine ClinicalTrials.gov.
  21. Denmeade, S, George D, Liu G, Peraire C, Geniaux A, Baton F, Ali T, Chetaille E (2011). "A phase I pharmacodynamics dose escalation study of steroid sulphatase inhibitor Irosustat in patients with prostate cancer". Eur. J. Cancer. 47: S499. doi:10.1016/S0959-8049(11)71998-0.
  22. "A Study of the Safety and Effectiveness of Irosustat When Added to an AI in ER+ve Locally Advanced or Metastatic Breast Cancer. (IRIS)". NIH US National Library of Medicine ClinicalTrials.gov.
  23. "A Study to Assess the Ability of a Novel Endocrine Treatment for Breast Cancer, Irosustat, to Slow Down Cancer Growth (IPET)". NIH US National Library of Medicine ClinicalTrials.gov.
  24. "A study looking at irosustat for early breast cancer (IPET)". Cancer Research UK.
  25. "A study looking at irosustat to treat advanced breast cancer (IRIS)". Cancer Research UK.
  26. "Sterix Ltd". Companies House.
  27. "Pharmacie : Ipsen acquiert le britannique Sterix". 2004.
  28. "Ordinary Fellows". Academy of Medical Sciences.
  29. "Academy of Europe". Chemical Sciences Section.
  30. "Chemical Biology Award". Royal Society of Chemistry.
  31. "The George and Christine Sosnovsky Award in Cancer Therapy Award Previous Winners". Royal Society of Chemistry.
  32. "Discovery of steroid sulphatase inhibitors recognised with GSK award". The Pharmaceutical Journal. 283: 295. 2009 – via URI: 10977876.
  33. "Malcolm Campbell Memorial Award, Previous Winners". Royal Society of Chemistry.
  34. "Interdisciplinary Prize 2010 Winner". Royal Society of Chemistry. 2010.
  35. "European Life Science Awards, 2012 Winners, Invesitgator of the Year".
  36. "BMCS Lectureship". Royal Society of Chemistry. 2015–2016.
  37. McPhee, Derek (2018). "Tu Youyou Award". Molecules. 23 (7): 1651. doi:10.3390/molecules23071651. PMC 6099563. PMID 29986395.
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