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Lipid phosphatase INPP5B: substrate cleavage with products C8-PtdIns4P, PO43˗ and Mg2+ (green), from X-ray structures with a synthetic lipid surrogate.
Our drug Irosustat (STX64/BN83495) translated "from bench to bedside": numerous international clinical trials in hundreds of male and female cancer patients and in healthy volunteers have shown clinical benefit.
Our new drug STX140 (left), now ready for clinical trial and shown (right) in complex with a protein target solved by X-ray crystallography, shows remarkable activity in pre-clinical models of cancer.
Barry V L Potter
MA DPhil DSc FRSC FRSB FMedSci
Professor of Medicinal and Biological Chemistry
- Wellcome Trust Senior Investigator
- Fellow of University College
Interdisciplinary application of Synthetic Organic & Biological Chemistry to Biology & Medicine
My research focuses on two key themes:
(i) The Chemistry of Cell Signalling
(ii) Anticancer Drug Design & Discovery
A unifying general theme is centered around cellular signalling processes and concerns both entities involved in endocrine signaling and its modulation in oncology and endocrinology, as well as the chemistry of signal transduction processes in general, but particularly those involving signalling through the elevation of Ca2+ by so-called "second messengers".
The work is characterised by a unifying focus to exploit chemical principles for intervention in Biology and Medicine. We aim to understand and exploit cell signalling processes in their broadest sense and to demonstrate the power of chemical synthesis for illuminating fundamental biology and for therapeutic intervention in medicine. Synthetic chemistry, particularly for bio-phosphates, nucleotides, second messengers and steroids is underpinned by biochemical assays, protein crystallography and by in silico computational design. We hope to uncover basic mechanisms, define new drug targets, design tailored synthetic drug candidates and make a therapeutic difference in areas of unmet medical need, particularly in cancer.
In Chemical Biology the group has long been a leader internationally in exploring Cellular Signalling Pathways involving inositol polyphosphates (see figure on the lipid phosphatase - lower left) and adenine nucleotides using synthetic tools. For the latter we focus particularly upon the Ca2+ - releasing messengers cyclic adenosine 5'-diphosphate ribose (cADPR), adenosine 5'-diphosphate ribose (ADPR - see animation left) and nicotinic acid adenine-5'-diphosphate-2'-phosphate (NAADP). We have been continuously funded for over 20 years by the Wellcome Trust through Project and Programme grants and more recently via a Senior Investigator Award.
In Medicinal Chemistry we have also achieved the rare goal of successful Academic Drug Discovery. We have defined novel therapeutic concepts and drug targets, pioneered a new structural motif for applications in oncology and women’s health and translated “first-in class” agents from the academic laboratory to 19 Phase I and II human clinical trials to date. This was facilitated through the founding of the spin-out company Sterix Ltd that was acquired by big pharma with whom we founded a multi-£M academic-industry partnership. Our drugs have been, or are currently in, clinical trials in metastatic breast cancer, endometrial cancer, prostate cancer and endometriosis and have demonstrated clinical benefit in cancer patients, including stable disease, responses and increased progression-free survival. Notable here are the steroid sulfatase inhibitors Irosustat (STX64) and PGL2001 and our new multi-targeting drug STX140 (see figures lower left).
I am a member of the Cancer Research UK Oxford Centre. Our future aims are to translate STX140 into the clinic for application in hormone-independent cancers and, using such tailored agents, to pioneer clinically the wider applications of multi-targeting drugs in hormone-dependent cancers, particularly via our concept of dual aromatase-sulfatase inhibition.
In recent years we have also developed a research interest in the discovery of new antibiotic candidates and have designed candidate antibacterial series with activities at the low ug/ml level, appropriate for further optimisation.
I am a Fellow of the Royal Society of Chemistry, Royal Society of Biology and an elected Member of Academia Europaea and the UK Academy of Medical Sciences. I am on or have been on numerous editorial boards including the ACS Journal of Medicinal Chemistry, AACR Molecular Cancer Therapeutics, ChemMedChem, Journal of Steroid Biochemistry & Molecular Biology (as Associate Editor) and Biochemical Journal's BJChemBio (as an Editor). I am also a Visiting Professor at the University of Bath and a member of the Scientific Advisory Boards of the Lister Institute of Preventive Medicine and the Institute of Chemistry and Biochemistry, Czech Academy of Sciences, Prague. I take an active role in the welfare and mentoring of graduates at University College as a Special Supernumerary Fellow.
Work from my group has been recognized by several Royal Society of Chemistry and industrial medals and prizes: RSC Medal for Chemical Biology (2007); RSC George and Christine Sosnovsky Medal (2007/8); RSC Malcolm Campbell Medal (2009); GlaxoSmithKline International Achievement Award (2009); RSC Interdisciplinary Medal (2010); European Life Sciences Award (2012); RSC-BMCS Medicinal Chemistry Lectureship (2015/16).
RECENT & UPCOMING EXTERNAL LECTURES
Advances in Drug Discovery 2017: Academic Drug Discovery, Wellcome Genome Campus, Hinxton, Cambridge, March 2017
Targeting Steroid Sulfation Pathways: Society for Endocrinology Conference, Birmingham, April 2017 (Keynote Lecture)
American Chemical Society-MEDI/European Federation for Medicinal Chemistry: Frontiers in Medicinal Chemistry Symposium, Drugs Discovered in Academia, Philadelphia, USA, June 2017
Gordon Research Conference on Drug Metabolism, Holderness, Plymouth, New Hampshire, USA, July 2017