In his drug design and discovery work one of the academically discovered "first-in-class" clinical drug targets identified was steroid sulfatase (STS)[8] and the first potent inhibitor was designed and synthesized by the Potter research group as the steroidal sulfamate EMATE.[9] Such synthetic active-site-directed, irreversible, time-dependent steroidal and non-steroidal inactivators of the enzyme progressed to clinical trials [10] 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) [11][12][13] and E2MATE (PGL2001) that have completed many clinical trials in the UK, Europe, USA and Australia in women's health, including for hormone replacement therapy and endometriosis,[14][15] post-menopausal ER+ hormone dependent breast cancer,[16][17][18][19][20] advanced/metastatic or recurrent estrogen receptor-positive endometrial cancer[21][22] and castration-resistant prostate cancer[23][24] and Irosustat was also evaluated as a combination therapy with an oral epidermal growth factor receptortyrosine kinase inhibitor for the Treatment of Non-Small Cell Lung Cancer Patients.[25] Irosustat is still progressing clinically. E2MATE/PGL2001 was well tolerated and for endometriosis 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.[15] A Phase II, multicentre, randomised, two-arm, parallel group, double-blind, placebo controlled, clinical study was initiated.[14] 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 [26] and IPET [27] breast cancer clinical trials [19][20] met their clinical endpoints; results were discussed [28][29] 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 [30] jointly between the University of Bath and Imperial College, London and was Director of Medicinal Chemistry and Chief Scientific Officer. Sterix Ltd pioneered inter alia the first human clinical trials of a steroid sulfatase inhibitor in breast cancer patients [16] and was acquired by the French Ipsen Group in 2004.[31]
It has been demonstrated that oral treatment with the STS inhibitor Irosustat alleviates the symptoms of Alzheimer's disease in a murine model, indicating that the drug passes the blood–brain barrier. STS inhibitors could therefore potentially be employed to treat such ageing and ageing-associated diseases, including Huntington’s and Parkinson’s diseases.[32] The Spanish spin-out company ONESTX [33] will pursue clinical application to such pathologies with STX64/Irosustat, both alone and in combination with neurosteroids.
Because of dual effects on stimulation of bone formation and inhibition of bone resorption Nexyon Biotech (Korea) is taking sulfatase inhibition into phase 2 clinical trials for osteogenesis imperfecta[34]
In 2020-2021 a themed journal issue was dedicated to Professor Potter entitled: "From Cell Signalling to Anticancer Drug Discovery".[35]
As of January 2023, Potter has published more than 550 articles in peer-reviewed journals, with many of his papers appearing in highly selective journals and is inventor of 45 granted US patents. His work has been cited over 23,000 times and he has an h-index of 74 and an i10 index of 420.[36]
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.[38]
^Brock, William H. (2018). Looking Back. Hove County Grammar School for Boys 1936-73. Surrey: Grosvenor House Publishing Ltd. pp. 247–8. ISBN978-1-78623-155-0.
^ abPohl, 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. PMID24604234. S2CID206805308.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ abStanway, 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. PMID16533785. S2CID1526070.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^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. PMID23797179. S2CID20060727.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
