Prof Chas Bountra

Research Area: Protein Science and Structural Biology
Technology Exchange: Computational biology, Crystallography, Drug discovery, Immunohistochemistry and In vivo imaging
Scientific Themes: Protein Science & Structural Biology and Physiology, Cellular & Molecular Biology
Keywords: target validation, drug discovery, translational science, structural biology, chemical probes and epigenetics
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SGC Oxford Chief Scientist

Chas Bountra, PhD

Chas is Professor of Translational Medicine in the Nuffield Department of Clinical Medicine and Associate Member of the Department of Pharmacology at the University of Oxford. He is also a Visiting Professor in Neuroscience and Mental Health at Imperial College, London. Chas is an invited expert on several government and charitable research funding bodies, and an advisor for many academic, biotech and pharma drug discovery programmes.

Prior to coming back to Oxford, Chas was Vice President and Head of Biology at GlaxoSmithKline. He was involved in the identification of more than 40 clinical candidates for many gastro-intestinal, inflammatory and neuro-psychiatric diseases. More than 20 of these molecules progressed into patient studies and more than five of these delivered successful “Proof of Concept” data and hence progressed into late stage development. He was involved in the launch and development of the first treatment for Irritable Bowel Syndrome (Alosetron) and was the first to show that neurokinin NK1 antagonists are anti-emetic in preclinical and clinical studies.

His current interests are i) using X ray structures of novel human proteins to generate small molecule inhibitors, screening in human cells to identify novel targets for drug discovery, and then developing clinical candidates for evaluation in patients, pre-competitively ii) focussing on epigenetic and genetically identified proteins, because these are likely to represent better targets for drug discovery, for many cancer, inflammatory, metabolic and neuro-psychiatric diseases iii) working with colleagues in Oxford to build major programmes in rare diseases and  in Alzheimers Disease, and creating a “BioEscalator” for the rapid translation of SGC science and iv) building stronger links with local hospitals, patient groups, regulatory agencies, private investors, CROs, biotechs and large pharma companies, to create a new, more efficient ecosystem for pioneer drug discovery.

Chas believes the SGC has become a leader in human protein structural biology and epigenetics chemical biology, and is arguably one of the most successful open innovation, public – private partnerships  in the world. Furthermore, with the many recent local developments (Target Discovery Institute, Kennedy Institute, Dementia Institute), he believes Oxford is emerging as one of the major academic drug discovery centres in Europe.

He has given over 300 invited lectures.  In 2012 he was voted one of the “top innovators in the industry”.

Name Department Institution Country
Prof Christopher Schofield Chemistry Oxford University United Kingdom
Rob Klose University of Oxford United Kingdom
Chris Austin National Chemical Genomic Centre, NIH, Washington United States
Tim Willson GlaxoSmithKline United States
David LLoyd Trinity College, Dublin Ireland
Luke O'Neill Trinity College, Dublin Ireland
David Gavaghan University of Oxford United Kingdom
Prof Liz Carpenter Structural Genomics Consortium University of Oxford United Kingdom
Dr Brian D Marsden Structural Genomics Consortium University of Oxford United Kingdom
Prof Stefan Knapp Structural Genomics Consortium University of Oxford United Kingdom
Dr Alex Bullock Structural Genomics Consortium University of Oxford United Kingdom
Dr Frank von Delft Structural Genomics Consortium University of Oxford United Kingdom
Dr Nicola A Burgess Brown Structural Genomics Consortium University of Oxford United Kingdom
Dr Opher Gileadi Structural Genomics Consortium University of Oxford United Kingdom
Dr Panagis Filippakopoulos Structural Genomics Consortium University of Oxford United Kingdom
Dr Paul Brennan Target Discovery Institute University of Oxford United Kingdom
Dr Susanne Muller-Knapp Structural Genomics Consortium University of Oxford United Kingdom
Dr Wyatt W Yue Structural Genomics Consortium University of Oxford United Kingdom

Grundy R, James L, Bountra C, Harrison T. 2014. Reconfiguring drug discovery through innovative partnerships Drug Discovery World, 15 (4), pp. 70-74. Read abstract

Attrition rates in drug discovery and development remain stubbornly high, despite large investments by the pharmaceutical industry.The cost of developing a new drug has been estimated at between $1.3 billion and upwards of $4 billion, if one takes into account the cost of failed development candidates'. Hide abstract

Borsook D, Hargreaves R, Bountra C, Porreca F. 2014. Lost but making progress--Where will new analgesic drugs come from? Sci Transl Med, 6 (249), pp. 249sr3. Read abstract | Read more

There is a critical need for effective new pharmacotherapies for pain. The paucity of new drugs successfully reaching the clinic calls for a reassessment of current analgesic drug discovery approaches. Many points early in the discovery process present significant hurdles, making it critical to exploit advances in pain neurobiology to increase the probability of success. In this review, we highlight approaches that are being pursued vigorously by the pain community for drug discovery, including innovative preclinical pain models, insights from genetics, mechanistic phenotyping of pain patients, development of biomarkers, and emerging insights into chronic pain as a disorder of both the periphery and the brain. Collaborative efforts between pharmaceutical, academic, and public entities to advance research in these areas promise to de-risk potential targets, stimulate investment, and speed evaluation and development of better pain therapies. Hide abstract

Rice AS, Dworkin RH, McCarthy TD, Anand P, Bountra C, McCloud PI, Hill J, Cutter G et al. 2014. EMA401, an orally administered highly selective angiotensin II type 2 receptor antagonist, as a novel treatment for postherpetic neuralgia: a randomised, double-blind, placebo-controlled phase 2 clinical trial. Lancet, 383 (9929), pp. 1637-1647. Read abstract | Read more

BACKGROUND: Existing treatments for postherpetic neuralgia, and for neuropathic pain in general, are limited by modest efficacy and unfavourable side-effects. The angiotensin II type 2 receptor (AT2R) is a new target for neuropathic pain. EMA401, a highly selective AT2R antagonist, is under development as a novel neuropathic pain therapeutic agent. We assessed the therapeutic potential of EMA401 in patients with postherpetic neuralgia. METHODS: In this multicentre, placebo-controlled, double-blind, randomised, phase 2 clinical trial, we enrolled patients (aged 22-89 years) with postherpetic neuralgia of at least 6 months' duration from 29 centres across six countries. We randomly allocated 183 participants to receive either oral EMA401 (100 mg twice daily) or placebo for 28 days. Randomisation was done according to a centralised randomisation schedule, blocked by study site, which was generated by an independent, unmasked statistician. Patients and staff at each site were masked to treatment assignment. We assessed the efficacy, safety, and pharmacokinetics of EMA401. The primary efficacy endpoint was change in mean pain intensity between baseline and the last week of dosing (days 22-28), measured on an 11-point numerical rating scale. The primary efficacy analysis was intention to treat. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12611000822987. FINDINGS: 92 patients were assigned to EMA401 and 91 were assigned to placebo. The patients given EMA401 reported significantly less pain compared with baseline values in the final week of treatment than did those given placebo (mean reductions in pain scores -2.29 [SD 1.75] vs -1.60 [1.66]; difference of adjusted least square means -0.69 [SE 0.25]; 95% CI -1.19 to -0.20; p=0.0066). No serious adverse events related to EMA401 occurred. Overall, 32 patients reported 56 treatment-emergent adverse events in the EMA401 group compared with 45 such events reported by 29 patients given placebo. INTERPRETATION: EMA401 (100 mg twice daily) provides superior relief of postherpetic neuralgia compared with placebo at the end of 28 days of treatment. EMA401 was well tolerated by patients. FUNDING: Spinifex Pharmaceuticals. Hide abstract

Picaud S, Wells C, Felletar I, Brotherton D, Martin S, Savitsky P, Diez-Dacal B, Philpott M et al. 2013. RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain. Proc Natl Acad Sci U S A, 110 (49), pp. 19754-19759. Read abstract | Read more

Bromodomains have emerged as attractive candidates for the development of inhibitors targeting gene transcription. Inhibitors of the bromo and extraterminal (BET) family recently showed promising activity in diverse disease models. However, the pleiotropic nature of BET proteins regulating tissue-specific transcription has raised safety concerns and suggested that attempts should be made for domain-specific targeting. Here, we report that RVX-208, a compound currently in phase II clinical trials, is a BET bromodomain inhibitor specific for second bromodomains (BD2s). Cocrystal structures revealed binding modes of RVX-208 and its synthetic precursor, and fluorescent recovery after photobleaching demonstrated that RVX-208 displaces BET proteins from chromatin. However, gene-expression data showed that BD2 inhibition only modestly affects BET-dependent gene transcription. Our data demonstrate the feasibility of specific targeting within the BET family resulting in different transcriptional outcomes and highlight the importance of BD1 in transcriptional regulation. Hide abstract

Newey PJ, Gorvin CM, Cleland SJ, Willberg CB, Bridge M, Azharuddin M, Drummond RS, van der Merwe PA, Klenerman P, Bountra C, Thakker RV. 2013. Mutant prolactin receptor and familial hyperprolactinemia. N Engl J Med, 369 (21), pp. 2012-2020. Read abstract | Read more

Hyperprolactinemia that is not associated with gestation or the puerperium is usually due to tumors in the anterior pituitary gland and occurs occasionally in hereditary multiple endocrine neoplasia syndromes. Here, we report data from three sisters with hyperprolactinemia, two of whom presented with oligomenorrhea and one with infertility. These symptoms were not associated with pituitary tumors or multiple endocrine neoplasia but were due to a heterozygous mutation in the prolactin receptor gene, PRLR, resulting in an amino acid change from histidine to arginine at codon 188 (His188Arg). This substitution disrupted the high-affinity ligand-binding interface of the prolactin receptor, resulting in a loss of downstream signaling by Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5). Thus, the familial hyperprolactinemia appears to be due to a germline, loss-of-function mutation in PRLR, resulting in prolactin insensitivity. Hide abstract

Shintre CA, Pike AC, Li Q, Kim JI, Barr AJ, Goubin S, Shrestha L, Yang J et al. 2013. Structures of ABCB10, a human ATP-binding cassette transporter in apo- and nucleotide-bound states. Proc Natl Acad Sci U S A, 110 (24), pp. 9710-9715. Read abstract | Read more

ABCB10 is one of the three ATP-binding cassette (ABC) transporters found in the inner membrane of mitochondria. In mammals ABCB10 is essential for erythropoiesis, and for protection of mitochondria against oxidative stress. ABCB10 is therefore a potential therapeutic target for diseases in which increased mitochondrial reactive oxygen species production and oxidative stress play a major role. The crystal structure of apo-ABCB10 shows a classic exporter fold ABC transporter structure, in an open-inwards conformation, ready to bind the substrate or nucleotide from the inner mitochondrial matrix or membrane. Unexpectedly, however, ABCB10 adopts an open-inwards conformation when complexed with nonhydrolysable ATP analogs, in contrast to other transporter structures which adopt an open-outwards conformation in complex with ATP. The three complexes of ABCB10/ATP analogs reported here showed varying degrees of opening of the transport substrate binding site, indicating that in this conformation there is some flexibility between the two halves of the protein. These structures suggest that the observed plasticity, together with a portal between two helices in the transmembrane region of ABCB10, assist transport substrate entry into the substrate binding cavity. These structures indicate that ABC transporters may exist in an open-inwards conformation when nucleotide is bound. We discuss ways in which this observation can be aligned with the current views on mechanisms of ABC transporters. Hide abstract

Quigley A, Dong YY, Pike AC, Dong L, Shrestha L, Berridge G, Stansfeld PJ, Sansom MS et al. 2013. The structural basis of ZMPSTE24-dependent laminopathies. Science, 339 (6127), pp. 1604-1607. Read abstract | Read more

Mutations in the nuclear membrane zinc metalloprotease ZMPSTE24 lead to diseases of lamin processing (laminopathies), such as the premature aging disease progeria and metabolic disorders. ZMPSTE24 processes prelamin A, a component of the nuclear lamina intermediate filaments, by cleaving it at two sites. Failure of this processing results in accumulation of farnesylated, membrane-associated prelamin A. The 3.4 angstrom crystal structure of human ZMPSTE24 has a seven transmembrane α-helical barrel structure, surrounding a large, water-filled, intramembrane chamber, capped by a zinc metalloprotease domain with the catalytic site facing into the chamber. The 3.8 angstrom structure of a complex with a CSIM tetrapeptide showed that the mode of binding of the substrate resembles that of an insect metalloprotease inhibitor in thermolysin. Laminopathy-associated mutations predicted to reduce ZMPSTE24 activity map to the zinc metalloprotease peptide-binding site and to the bottom of the chamber. Hide abstract

Anand U, Facer P, Yiangou Y, Sinisi M, Fox M, McCarthy T, Bountra C, Korchev YE, Anand P. 2013. Angiotensin II type 2 receptor (AT2 R) localization and antagonist-mediated inhibition of capsaicin responses and neurite outgrowth in human and rat sensory neurons. Eur J Pain, 17 (7), pp. 1012-1026. Read abstract | Read more

BACKGROUND: The angiotensin II (AngII) receptor subtype 2 (AT2 R) is expressed in sensory neurons and may play a role in nociception and neuronal regeneration. METHODS: We used immunostaining with characterized antibodies to study the localization of AT2 R in cultured human and rat dorsal root ganglion (DRG) neurons and a range of human tissues. The effects of AngII and AT2 R antagonist EMA401 on capsaicin responses in cultured human and rat (DRG) neurons were measured with calcium imaging, on neurite length and density with Gap43 immunostaining, and on cyclic adenosine monophosphate (cAMP) expression using immunofluorescence. RESULTS: AT2 R expression was localized in small-/medium-sized cultured neurons of human and rat DRG. Treatment with the AT2 R antagonist EMA401 resulted in dose-related functional inhibition of capsaicin responses (IC50  = 10 nmol/L), which was reversed by 8-bromo-cAMP, and reduced neurite length and density; AngII treatment significantly enhanced capsaicin responses, cAMP levels and neurite outgrowth. The AT1 R antagonist losartan had no effect on capsaicin responses. AT2 R was localized in sensory neurons of human DRG, and nerve fibres in peripheral nerves, skin, urinary bladder and bowel. A majority sub-population (60%) of small-/medium-diameter neuronal cells were immunopositive in both control post-mortem and avulsion-injured human DRG; some very small neurons appeared to be intensely immunoreactive, with TRPV1 co-localization. While AT2 R levels were reduced in human limb peripheral nerve segments proximal to injury, they were preserved in painful neuromas. CONCLUSIONS: AT2 R antagonists could be particularly useful in the treatment of chronic pain and hypersensitivity associated with abnormal nerve sprouting. Hide abstract

Kruidenier L, Chung CW, Cheng Z, Liddle J, Che K, Joberty G, Bantscheff M, Bountra C et al. 2012. A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature, 488 (7411), pp. 404-408. Read abstract | Read more

The jumonji (JMJ) family of histone demethylases are Fe2+- and α-ketoglutarate-dependent oxygenases that are essential components of regulatory transcriptional chromatin complexes. These enzymes demethylate lysine residues in histones in a methylation-state and sequence-specific context. Considerable effort has been devoted to gaining a mechanistic understanding of the roles of histone lysine demethylases in eukaryotic transcription, genome integrity and epigenetic inheritance, as well as in development, physiology and disease. However, because of the absence of any selective inhibitors, the relevance of the demethylase activity of JMJ enzymes in regulating cellular responses remains poorly understood. Here we present a structure-guided small-molecule and chemoproteomics approach to elucidating the functional role of the H3K27me3-specific demethylase subfamily (KDM6 subfamily members JMJD3 and UTX). The liganded structures of human and mouse JMJD3 provide novel insight into the specificity determinants for cofactor, substrate and inhibitor recognition by the KDM6 subfamily of demethylases. We exploited these structural features to generate the first small-molecule catalytic site inhibitor that is selective for the H3K27me3-specific JMJ subfamily. We demonstrate that this inhibitor binds in a novel manner and reduces lipopolysaccharide-induced proinflammatory cytokine production by human primary macrophages, a process that depends on both JMJD3 and UTX. Our results resolve the ambiguity associated with the catalytic function of H3K27-specific JMJs in regulating disease-relevant inflammatory responses and provide encouragement for designing small-molecule inhibitors to allow selective pharmacological intervention across the JMJ family. Hide abstract

Arrowsmith CH, Bountra C, Fish PV, Lee K, Schapira M. 2012. Epigenetic protein families: A new frontier for drug discovery Nature Reviews Drug Discovery, 11 (5), pp. 384-400. Read abstract | Read more

Epigenetic regulation of gene expression is a dynamic and reversible process that establishes normal cellular phenotypes but also contributes to human diseases. At the molecular level, epigenetic regulation involves hierarchical covalent modification of DNA and the proteins that package DNA, such as histones. Here, we review the key protein families that mediate epigenetic signalling through the acetylation and methylation of histones, including histone deacetylases, protein methyltransferases, lysine demethylases, bromodomain-containing proteins and proteins that bind to methylated histones. These protein families are emerging as druggable classes of enzymes and druggable classes of proteing-protein interaction domains. In this article, we discuss the known links with disease, basic molecular mechanisms of action and recent progress in the pharmacological modulation of each class of proteins. © 2012 Macmillan Publishers Limited. All rights reserved. Hide abstract

Norman TC, Bountra C, Edwards AM, Yamamoto KR, Friend SH. 2011. Leveraging crowdsourcing to facilitate the discovery of new medicines. Sci Transl Med, 3 (88), pp. 88mr1. Read abstract | Read more

Gloomy predictions about the future of pharma have forced the industry to investigate alternative models of drug discovery. Public-private partnerships (PPPs) have the potential to revitalize the discovery and development of first-in-class therapeutics. The new PPP Arch2POCM hopes to foster biomedical innovation through precompetitive validation of pioneer therapeutic targets for human diseases. In this meeting report, we capture insights garnered from the April 2011 Arch2POCM conference. Hide abstract

Norman T, Edwards A, Bountra C, Friend S. 2011. The precompetitive space: time to move the yardsticks. Sci Transl Med, 3 (76), pp. 76cm10. Read abstract | Read more

Industry, government, patient advocacy groups, public funders, and academic thought leaders met in Toronto, Canada, to set into motion an initiative that addresses some of the scientific and organizational challenges of modern therapeutics discovery. What emerged from the meeting was a public-private partnership that seeks to establish proof of clinical mechanism (POCM) for selected "pioneer" disease targets using lead compounds-all accomplished in the precompetitive space. The group will reconvene in April 2011 to create a business plan that specifies the generation of two positive POCM results per year. Hide abstract

Bountra C, Oppermann U, Heightman TD. 2011. Animal models of epigenetic regulation in neuropsychiatric disorders. Curr Top Behav Neurosci, 7 (1), pp. 281-322. Read abstract | Read more

Epigenetics describes the phenomenon of heritable changes in gene regulation that are governed by non-Mendelian processes, primarily through biochemical modifications to chromatin structure that occur during cell development and differentiation. Numerous lines of evidence link abnormal levels of chromatin modifications (either to DNA, histones, or both) in patients with a wide variety of diseases including cancer, psychiatry, neurodegeneration, metabolic and inflammatory disorders. Drugs that target the proteins controlling chromatin modifications can modulate the expression of clusters of genes, potentially offering higher therapeutic efficacy than classical agents with single target pharmacologies that are susceptible to biochemical pathway degeneracy. Here, we summarize recent research linking epigenetic dysregulation with diseases in neurosciences, the application of relevant animal models, and the potential for small molecule modulator development to facilitate target discovery, validation and translation into clinical treatments. Hide abstract

Sanger GJ, Chang L, Bountra C, Houghton LA. 2010. Challenges and prospects for pharmacotherapy in functional gastrointestinal disorders. Therap Adv Gastroenterol, 3 (5), pp. 291-305. Read abstract | Read more

Functional gastrointestinal disorders, such as irritable bowel syndrome and functional dyspepsia, are complex conditions with multiple factors contributing to their pathophysiology. As a consequence they are difficult to treat and have posed significant challenges to the pharmaceutical industry when trying to develop new and effective treatments. This review provides an overview of these difficulties and how the industry is reshaping its drug developmental strategies. It describes some of the more significant and encouraging advances that have occurred, and discusses how future research might embrace the opportunities provided by advances in genetic and in particular, epigenetic research. Hide abstract

Toronto International Data Release Workshop Authors, Birney E, Hudson TJ, Green ED, Gunter C, Eddy S, Rogers J, Harris JR et al. 2009. Prepublication data sharing. Nature, 461 (7261), pp. 168-170. Read abstract | Read more

Rapid release of prepublication data has served the field of genomics well. Attendees at a workshop in Toronto recommend extending the practice to other biological data sets. Hide abstract

Swarbrick ME, Beswick PJ, Gleave RJ, Green RH, Bingham S, Bountra C, Carter MC, Chambers LJ et al. 2009. Identification of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidinyl] amines and ethers as potent and selective cyclooxygenase-2 inhibitors. Bioorg Med Chem Lett, 19 (15), pp. 4504-4508. Read abstract | Read more

A novel series of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidine-based cyclooxygenase-2 (COX-2) inhibitors, which have a different arrangement of substituents compared to the more common 1,2-diarylheterocycle based molecules, have been discovered. For example, 2-(butyloxy)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (47), a member of the 2-pyrimidinyl ether series, has been shown to be a potent and selective inhibitor with a favourable pharmacokinetic profile, high brain penetration and good efficacy in rat models of hypersensitivity. Hide abstract

Beswick PJ, Blackaby AP, Bountra C, Brown T, Browning K, Campbell IB, Corfield J, Gleave RJ et al. 2009. Identification and optimisation of a novel series of pyrimidine based cyclooxygenase-2 (COX-2) inhibitors. Utilisation of a biotransformation approach. Bioorg Med Chem Lett, 19 (15), pp. 4509-4514. Read abstract | Read more

Many years of work have been invested in the identification of potent and selective COX-2 inhibitors for the treatment of chronic inflammatory pain. One issue faced by workers is the balance between the lipophilicity required for potent enzyme inhibition and the physical properties necessary for drug absorption and distribution in vivo. Frequently approaches to reduce lipophilicity through introduction of polar functionality is hampered by highly challenging chemistry to prepare key molecules. We have complemented traditional synthetic chemistry with a biotransformations approach which efficiently provided access to an array of key target molecules. Hide abstract

Edwards AM, Bountra C, Kerr DJ, Willson TM. 2009. Open access chemical and clinical probes to support drug discovery. Nat Chem Biol, 5 (7), pp. 436-440. Read abstract | Read more

Drug discovery resources in academia and industry are not used efficiently, to the detriment of industry and society. Duplication could be reduced, and productivity could be increased, by performing basic biology and clinical proofs of concept within open access industry-academia partnerships. Chemical biologists could play a central role in this effort. Hide abstract


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