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 FRSB FRSC MAE 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 signalling 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, particularly stereochemistry. We aim to understand and exploit cell signalling processes in their broadest sense and to demonstrate the power of chemical synthesis and chirality 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 is an international leader in exploring Cellular Signalling Pathways involving chiral 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 and teaching of Biomedical Science students as a Special Supernumerary Fellow.
Work from my group has been recognized by several Royal Society of Chemistry (RSC), industrial and other 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); Tu Youyou Award in Medicinal & Natural Product Chemistry (2018).
Quinazolinone-Based Anticancer Agents: Synthesis, Antiproliferative SAR, Antitubulin Activity, and Tubulin Co-crystal Structure.
Dohle W. et al, (2018), J Med Chem, 61, 1031 - 1044
2'-Deoxyadenosine 5'-diphosphoribose is an endogenous TRPM2 superagonist.
Fliegert R. et al, (2017), Nat Chem Biol, 13, 1036 - 1044
Insights into the activation mechanism of class I HDAC complexes by inositol phosphates.
Watson PJ. et al, (2016), Nat Commun, 7
Crystal Structures of Type-II Inositol Polyphosphate 5-Phosphatase INPP5B with Synthetic Inositol Polyphosphate Surrogates Reveal New Mechanistic Insights for the Inositol 5-Phosphatase Family.
Mills SJ. et al, (2016), Biochemistry, 55, 1384 - 1397
A synthetic polyphosphoinositide headgroup surrogate in complex with SHIP2 provides a rationale for drug discovery.
Mills SJ. et al, (2012), ACS Chem Biol, 7, 822 - 828
NAADP-mediated Ca2+ signaling via type 1 ryanodine receptor in T cells revealed by a synthetic NAADP antagonist.
Dammermann W. et al, (2009), Proc Natl Acad Sci U S A, 106, 10678 - 10683
Synthesis of terminal ribose analogues of adenosine 5'-diphosphate ribose (ADPR) as probes for the Transient Receptor Potential (TRP) cation channel TRPM2.
Baszczyňski O. et al, (2019), J Org Chem
Different substrate specificities of the two ADPR binding sites in TRPM2 channels of Nematostella vectensis and the role of IDPR.
Kühn FJP. et al, (2019), Sci Rep, 9
3,17β-Bis-sulfamoyloxy-2-methoxyestra-1,3,5(10)-triene (STX140) and Non-Steroidal Sulfamate Derivatives Inhibit Carbonic Anhydrase IX: Structure-Activity Optimization for Isoform Selectivity.
Andring J. et al, (2019), J Med Chem
Small Molecule Antagonists of NAADP-Induced Ca2+ Release in T-Lymphocytes Suggest Potential Therapeutic Agents for Autoimmune Disease.
Zhang B. et al, (2018), Sci Rep, 8
Simple synthesis of 32P-labelled inositol hexakisphosphates for study of phosphate transformations.
Whitfield H. et al, (2018), Plant Soil, 427, 149 - 161
Steroid Sulfatase Inhibition by Aryl Sulfamates: Clinical Progress, Mechanism and Future Prospects.
Potter BVL., (2018), J Mol Endocrinol
RECENT & UPCOMING EXTERNAL LECTURES
Advances in Drug Discovery 2017: Academic Drug Discovery, Wellcome Genome Campus, Hinxton, Cambridge, March 2017 (Invited Speaker)
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 (Invited Speaker)
Gordon Research Conference on Drug Metabolism, Holderness, Plymouth, New Hampshire, USA, July 2017 (Invited Speaker)
Pharmaceutical Sciences Ph.D Day, Universities of Geneva & Lausanne, Geneva, Switzerland, June 2018 (Keynote Speaker)
International Association for Cellular Coenzymes (IACC) Symposium - Cellular Coenzymes in Health & Disease, London, July 2018 (Invited Speaker)
Facing Novel Challenges in Drug Discovery (MMCS2019), 2nd Molecules Medicinal Chemistry Symposium, Barcelona, May 2019 (Keynote Speaker)
SUPA 2019 Conference, Schloss Rauischholzhausen, Germany, April 2019 (Invited Speaker)
Lister Institute for Preventive Medicine Research Meeting, Oxford, Sept 2019 (Keynote Speaker)
ASPET 2020: American Society for Pharmacology & Therapeutics Annual Meeting, San Diego, USA, April 2020 (Invited Speaker)