Prof.Paul E. Brennan

Target Discovery Institute

Structural Genomics Consortium

Nuffield Department of Medicine

University of Oxford

Summary: I am aninnovative and successful medicinal chemistrywith diverse experience, a history of clinical candidate delivery and a strong background in synthetic organic, medicinal chemistry and chemical biology. While working for Pfizer and Amgen, I delivered advanced compounds in projects for most major disease targets: kinase inhibitors, GPCR agonists and antagonists, metabolic enzymes, ion channels and chromatin modifiers while working in the urology, oncology, allergy, respiratory and pain therapeutic areas.

As the principal investigator in medicinal chemistry at the Target Discovery Institute and Structural Genomics Consortium (SGC) in NDM, I lead the chemistry team dedicated to designing and synthesizing open-access small molecule probes, with a focus on epigenetic proteins. The probes discovered in my labs are used by hundreds of groups internationally to elucidate the mechanism of epigenetic regulation, one of the most exciting new areas of human biology.

In 2013, I joined a multidisciplinary team in the University of Oxford’s Target Discovery Institute. As leader of the medicinal chemistry group in the TDI,my group designs and synthesizes chemical probes to enable target discovery in oncology, inflammatory disease and dementia and develops new chemoproteomic and biophysical assays to characterize epigenetic inhibitors.

Since joining the University, I have collaborated extensively within NDM (SGC, TDI, BHF-CRE, Oncology, Ludwig) and NDORMS (Botnar, Kennedy) and built links between NDM and the chemistry department.

Research Experience

2013 - Present / Target Discovery Institute, University of Oxford.
Associate Professorof Medicinal Chemistry
  • Design and synthesis of chemical probes for oncology, inflammatory disease and dementia for drug targets discovery
  • Structure- and fragment-based drug design
  • Design and synthesis of custom fragment libraries
  • Biophysical assay development
  • Mass-spectroscopy and chemoproteomics
Work closely with other PI’s on phenotypic screening, mass spec based proteomics, cellular assays, yeast 3-hybrids, biophysics and protein crystallography for drug target discovery.
2011 - Present / Structural Genomics Consortium, University of Oxford.
Associate Professorof Medicinal Chemistry, leading a multidisciplinary group of 15 doctoral and post-doctoral medicinal chemists, biochemists and massspectrometrists.
  • Design and synthesis of small molecule epigenetic probes
  • Discovered >10 hit molecules for epigenetic probes
  • Discovered some of the first BET (BRD4) inhibitors; and the first non-BET bromodomains inhibitors (BRD7/9, PB1/SMARCA2/4, CREBBP/EP300, BRPF1B)
  • Designed Bromosporine, the first pan-bromodomain inhibitor
  • Design of selective lysine demethylase inhibitors
  • Protein production and assay development for methyl lysine reader domains (PHD, Tudor)
  • Initiated >50 new collaborations with research groups from diverse disciplines.

2005–2011 / Pfizer, Sandwich, UK. Senior Principal Scientist and chemistry team leader in urology, allergy and respiratory, epigenetics, leading a group of up to 4 medicinal and synthetic chemists.
  • Discovered a clinical candidate and a late-pre clinical candidate for incontinence and obesity in two programs for CNS active GPCR agonists
  • Discovered a late-pre clinical candidate GPCR antagonist for respiratory disease
  • Discovered hit compounds as ion channel antagonists for pain
  • Discovered a late pre-clinical candidate enzyme inhibitor for respiratory disease
  • Led an early project to discover an ubiquitin E3 ligase inhibitor for respiratory disease.

2003–2005 / Amgen, Thousand Oaks, California.
Research Scientist and chemistry team leader in oncology, leading a group of 2 medicinal chemists.
  • Discovered an advanced PLK serine/threonine kinase lead inhibitor for oncology
  • Optimized hit compounds in a tyrosine kinase inhibitor program for oncology to enable lead development.

2000 –2003 / University of Cambridge, Department of Chemistry.
Advisor: Professor Steven V. Ley
Post-doctoral Researcher and chemistry team leader, leading a group of 2-3 PHD students.
  • Invented a new synthesis route enabling the total synthesis of Rapamycin
  • Supervised a PHD student to develop the synthesis of oligosaccharides using clean chemistry
  • Collaborated with other post-doctoral researchers to utilize with Pd-containing Perovskites in Suzuki cross coupling reactions.

1998 / Pharmacopeia,Princeton, New Jersey. Summer Intern.
  • Multi-step organic synthesis
  • Solid-Phase combinatorial chemistry

1989–1991 / Genta Inc (now Promega), San Luis Obispo, California. Research Associate.
  • Synthesis and HPLC purification of anti-sense oligonucleotides
  • Synthesis of modified nucleosides

Education

1995 – 2000 / University of California, Berkeley
Advisor: Professor Paul A. Bartlett, Ph.D.
  • PhD in Organic Chemistry; awarded April 2000
  • Thesis title: I. Phosphinate Inhibitors of Peptidoglycan Biosynthesis.
II. Development of a New Ring System for Combinatorial Chemistry
1991 – 1995 / University of California, Davis
Advisor: Professor Mark J. Kurth, PhD
  • Bachelor of Science in Chemistry, with high honors; awarded June 1995
  • Awarded Most Outstanding Student in Organic Chemistry
  • Senior thesis title: Site Isolation Studies on Solid Support

Teaching at the University of Oxford

Centres for Doctoral Training (Sys. Approach to Biomed. Sci. – Industrial Doctoral Centre, Syn. for Bio.and Med., Life Sci. Interface)

  • Organise and teach a two-week drug discovery lecture course for first-year DPhil students from math, physics, computational, biological and chemistry backgrounds.

Department of Chemistry

  • Deliver five lectures annually for the Pharmaceutical Chemistry section of the years 3-4 curriculum.

DPhil Student Supervision

  • Acted as primary and co-supervisor for 3 completed DPhil students in the Chemistry Department. Primary supervisee was awarded a distinction on his thesis and won multiple best presentation awards for invited lectures.
  • Currently supervising 4 SABS-CDT DPhil candidates in the TDI and co-supervising 3 SABS-CDT students in the Chemistry Department and 1 in NDORMS.

Grant Funding

  • Co-investigator on IMI ULTRA-DD grant for SGC (£16 M over 5 years)
  • Co-author on Alzheimer’s Research UK O3DI grant for TDI (£10 M over 5 years)
  • Co-author on WT Phase 4 TEP grant for SGC (£9 M over 5 years)
  • Attracted 7 large industrial pharmaceutical to support the SGC (£14 M total over 4 years)
  • Named medicinal chemistry collaborator on 10 grant applications from NDM, NDORMS and Chemistry Department

Additional Professional Responsibilities

UK Medical Research Council

  • Development Pathway Funding Scheme review panel member
  • Review drug discovery grants for all medical areas from UK researchers

3D-Fragment Library Consortium – UK-based consortium of 7 academic drug discovery groups (Dundee, UCL, Beatson, ICR, MRCT, CRT, SGC)

  • Steering Committee member.

University of Oxford, Systems Approach to Biomedical Sciences -Centre for Doctoral Training

  • Scientific Management Committee member, representing the SGC

University of Oxford, Synthesis for Biology and Medicine- Centre for Doctoral Training

  • Leader of the New 3D Templates research focus package.
  • Facilitate project collaborations between Oxford academic and industrial chemists with a focus on novel 3D compounds

Invited External Lectures (2013-2015)

  • 2015– ELRIGNew Approaches to Phenotypic Screening;RSC-BMCS 5thFragment-based Drug Discovery; SCT 51stInternational Conference on Medicinal Chemistry (Plenary Lecture).
  • 2014 –Evotec, MRC ARM Workshop (Chair), Leeds University, IQPC Compound Libraries, Bayer, SCI Epigenetics, SCS 11th Swiss Course on Medicinal Chemistry, Janssen, Merck, Lilly, Novartis, Celgene, Mercachem, UNICAMP/Nature Chemical-Probe Based Open Science, Leo Pharma, Takeda, SMI 13th Advances and Progress in Drug Design,
  • 2013– RSC-CPA 4th Symposium on Medicinal Chemistry, Abbvie, Novartis-Shanghai, Shanghia Institute Materia Medica, Pfizer-Boston, University of North Carolina, Takeda- San Diego, Abbvie-Chicago, ACS 246th National Meeting, University of Reading Young Researchers Pharmaceutics and Bio-pharmaceutics (Keynote), Oxford DrugDesign2013, SMR Partnerships: Future Models for Drug Discovery, RSC 6th Anglo Swedish Medicinal Chemistry Symposium, Roche-Basel, RSC-IICT 2nd UK-India MedChem Congress.

Publications and Patents (2011-2015)

1.Hammitzsch, A.; Tallant, C.; Fedorov, O.; O’Mahony, A.; Brennan, P. E.; Hay, D. A.; Martinez, F. O.; Al-Mossawi, M. H.; de Wit, J.; Vecellio, M.; Wells, C.; Wordsworth, P.; Müller, S.; Knapp, S.; Bowness, P., CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses. Proc. Natl Acad. Sci.2015,112 (34), 10768-10773.

2.Hay, D. A.; Rogers, C. M.; Fedorov, O.; Tallant, C.; Martin, S.; Monteiro, O. P.; Muller, S.; Knapp, S.; Schofield, C. J.; Brennan, P. E., Design and synthesis of potent and selective inhibitors of BRD7 and BRD9 bromodomains. MedChemComm2015,6 (7), 1381-1386.

3.Bennett, J.; Fedorov, O.; Tallant, C.; Monteiro, O.; Meier, J.; Gamble, V.; Savitsky, P.; Nunez-Alonso, G. A.; Haendler, B.; Rogers, C.; Brennan, P. E.; Muller, S.; Knapp, S., Discovery of a Chemical Tool Inhibitor Targeting the Bromodomains of TRIM24 and BRPF. J Med Chem2015, 10.1021/acs.jmedchem.5b00458.

4.Clark, P. G. K.; Vieira, L. C. C.; Tallant, C.; Fedorov, O.; Singleton, D. C.; Rogers, C. M.; Monteiro, O. P.; Bennett, J. M.; Baronio, R.; Müller, S.; Daniels, D. L.; Méndez, J.; Knapp, S.; Brennan, P. E.; Dixon, D. J., LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor. Angew. Chem. Int. Ed. 2015,10.1002/anie.201501394R2.

5.England, K. S.; Tumber, A.; Krojer, T.; Scozzafava, G.; Ng, S. S.; Daniel, M.; Szykowska, A.; Che, K.; von Delft, F.; Burgess-Brown, N. A.; Kawamura, A.; Schofield, C. J.; Brennan, P. E., Optimisation of a triazolopyridine based histone demethylase inhibitor yields a potent and selective KDM2A (FBXL11) inhibitor. MedChemComm2014,5 (12), 1879-1886.

6.Hay, D. A.; Fedorov, O.; Martin, S.; Singleton, D. C.; Tallant, C.; Wells, C.; Picaud, S.; Philpott, M.; Monteiro, O. P.; Rogers, C. M.; Conway, S. J.; Rooney, T. P. C.; Tumber, A.; Yapp, C.; Filippakopoulos, P.; Bunnage, M. E.; Müller, S.; Knapp, S.; Schofield, C. J.; Brennan, P. E., Discovery and Optimization of Small-Molecule Ligands for the CBP/p300 Bromodomains. J. Amer. Chem. Soc2014,136 (26), 9308-9319.

7.Rooney, T. P.; Filippakopoulos, P.; Fedorov, O.; Picaud, S.; Cortopassi, W. A.; Hay, D. A.; Martin, S.; Tumber, A.; Rogers, C. M.; Philpott, M.; Wang, M.; Thompson, A. L.; Heightman, T. D.; Pryde, D. C.; Cook, A.; Paton, R. S.; Muller, S.; Knapp, S.; Brennan, P. E.; Conway, S. J., A Series of Potent CREBBP Bromodomain Ligands Reveals an Induced-Fit Pocket Stabilized by a Cation-pi Interaction. Angew. Chem. Int. Ed. 2014,53 (24), 6126-30.

8.Storer, R. I.; Brennan, P. E.; Brown, A. D.; Bungay, P. J.; Conlon, K. M.; Corbett, M. S.; DePianta, R. P.; Fish, P. V.; Heifetz, A.; Ho, D. K. H.; Jessiman, A. S.; McMurray, G.; de Oliveira, C. A. F.; Roberts, L. R.; Root, J. A.; Shanmugasundaram, V.; Shapiro, M. J.; Skerten, M.; Westbrook, D.; Wheeler, S.; Whitlock, G. A.; Wright, J., Multiparameter Optimization in CNS Drug Discovery: Design of Pyrimido[4,5-d]azepines as Potent 5-Hydroxytryptamine 2C (5-HT2C) Receptor Agonists with Exquisite Functional Selectivity over 5-HT2A and 5-HT2B Receptors. J. Med. Chem. 2014,57 (12), 5258-5269.

9.Guetzoyan, L.; Ingham, R. J.; Nikbin, N.; Rossignol, J.; Wolling, M.; Baumert, M.; Burgess-Brown, N. A.; Strain-Damerell, C. M.; Shrestha, L.; Brennan, P. E.; Fedorov, O.; Knapp, S.; Ley, S. V., Machine-assisted synthesis of modulators of the histone reader BRD9 using flow methods of chemistry and frontal affinity chromatography. MedChemComm2014,5 (4), 540-546.

10.Fedorov, O.; Lingard, H.; Wells, C.; Monteiro, O. P.; Picaud, S.; Keates, T.; Yapp, C.; Philpott, M.; Martin, S. J.; Felletar, I.; Marsden, B. D.; Filippakopoulos, P.; Müller, S.; Knapp, S.; Brennan, P. E., [1,2,4]Triazolo[4,3-a]phthalazines: Inhibitors of Diverse Bromodomains. J. Med. Chem. 2014,57 (2), 462-476.

11.Morley, A. D.; Pugliese, A.; Birchall, K.; Bower, J.; Brennan, P.; Brown, N.; Chapman, T.; Drysdale, M.; Gilbert, I. H.; Hoelder, S.; Jordan, A.; Ley, S. V.; Merritt, A.; Miller, D.; Swarbrick, M. E.; Wyatt, P. G., Fragment-based hit identification: thinking in 3D. Drug Discovery Today 2013,18 (23–24), 1221-1227.

12.Picaud, S.; Wells, C.; Felletar, I.; Brotherton, D.; Martin, S.; Savitsky, P.; Diez-Dacal, B.; Philpott, M.; Bountra, C.; Lingard, H.; Fedorov, O.; Müller, S.; Brennan, P. E.; Knapp, S.; Filippakopoulos, P., RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain. Proc. Natl Acad. Sci. 2013,110 (49), 19754-19759.

13.Picaud, S.; Da Costa, D.; Thanasopoulou, A.; Filippakopoulos, P.; Fish, P. V.; Philpott, M.; Fedorov, O.; Brennan, P.; Bunnage, M. E.; Owen, D. R.; Bradner, J. E.; Taniere, P.; O'Sullivan, B.; Müller, S.; Schwaller, J.; Stankovic, T.; Knapp, S., PFI-1, a Highly Selective Protein Interaction Inhibitor, Targeting BET Bromodomains. Cancer Res. 2013,73 (11), 3336-3346.

14.Hopkinson, R. J.; Tumber, A.; Yapp, C.; Chowdhury, R.; Aik, W.; Che, K. H.; Li, X. S.; Kristensen, J. B. L.; King, O. N. F.; Chan, M. C.; Yeoh, K. K.; Choi, H.; Walport, L. J.; Thinnes, C. C.; Bush, J. T.; Lejeune, C.; Rydzik, A. M.; Rose, N. R.; Bagg, E. A.; McDonough, M. A.; Krojer, T. J.; Yue, W. W.; Ng, S. S.; Olsen, L.; Brennan, P. E.; Oppermann, U.; Muller, S.; Klose, R. J.; Ratcliffe, P. J.; Schofield, C. J.; Kawamura, A., 5-Carboxy-8-hydroxyquinoline is a broad spectrum 2-oxoglutarate oxygenase inhibitor which causes iron translocation. Chem. Sci. 2013,4 (8), 3110-3117.

15.Hewings, D. S.; Fedorov, O.; Filippakopoulos, P.; Martin, S.; Picaud, S.; Tumber, A.; Wells, C.; Olcina, M. M.; Freeman, K.; Gill, A.; Ritchie, A. J.; Sheppard, D. W.; Russell, A. J.; Hammond, E. M.; Knapp, S.; Brennan, P. E.; Conway, S. J., Optimization of 3,5-Dimethylisoxazole Derivatives as Potent Bromodomain Ligands. J. Med. Chem. 2013,56 (8), 3217-3227.

16.Hay, D.; Fedorov, O.; Filippakopoulos, P.; Martin, S.; Philpott, M.; Picaud, S.; Hewings, D. S.; Uttakar, S.; Heightman, T. D.; Conway, S. J.; Knapp, S.; Brennan, P. E., The design and synthesis of 5- and 6-isoxazolylbenzimidazoles as selective inhibitors of the BET bromodomains. MedChemComm2013,4 (1), 140-144.

17.Yue, W.; Froese, D.; Brennan, P., The Role of Protein Structural Analysis in the Next Generation Sequencing Era. In Topics in Current Chemistry, Springer Berlin / Heidelberg: 2012;pp 1-32.

18.Rose, N. R.; Woon, E. C. Y.; Tumber, A.; Walport, L. J.; Chowdhury, R.; Li, X. S.; King, O. N. F.; Lejeune, C.; Ng, S. S.; Krojer, T.; Chan, M. C.; Rydzik, A. M.; Hopkinson, R. J.; Che, K. H.; Daniel, M.; Strain-Damerell, C.; Gileadi, C.; Kochan, G.; Leung, I. K. H.; Dunford, J.; Yeoh, K. K.; Ratcliffe, P. J.; Burgess-Brown, N.; von Delft, F.; Muller, S.; Marsden, B.; Brennan, P. E.; McDonough, M. A.; Oppermann, U.; Klose, R. J.; Schofield, C. J.; Kawamura, A., Plant Growth Regulator Daminozide Is a Selective Inhibitor of Human KDM2/7 Histone Demethylases. J. Med. Chem. 2012,55 (14), 6639-6643.

19.Hewings, D. S.; Rooney, T. P. C.; Jennings, L. E.; Hay, D. A.; Schofield, C. J.; Brennan, P. E.; Knapp, S.; Conway, S. J., Progress in the Development and Application of Small Molecule Inhibitors of Bromodomain–Acetyl-lysine Interactions. J. Med. Chem. 2012,55 (22), 9393-9413.

20.Fish, P. V.; Filippakopoulos, P.; Bish, G.; Brennan, P. E.; Bunnage, M. E.; Cook, A. S.; Federov, O.; Gerstenberger, B. S.; Jones, H.; Knapp, S.; Marsden, B.; Nocka, K.; Owen, D. R.; Philpott, M.; Picaud, S.; Primiano, M. J.; Ralph, M. J.; Sciammetta, N.; Trzupek, J. D., Identification of a Chemical Probe for Bromo and Extra C-Terminal Bromodomain Inhibition through Optimization of a Fragment-Derived Hit. J. Med. Chem. 2012,55 (22), 9831-9837.

21.Brennan, P.; Filippakopoulos, P.; Knapp, S., The therapeutic potential of acetyl-lysine and methyl-lysine effector domains.Drug Discovery Today: Ther. Strategies 2012,9 (2–3), e101-e110.

22.Ho, D. K. H.; Chan, L.; Hooper, A.; Brennan, P. E., A general and mild two-step procedure for the synthesis of aryl and heteroaryl sulfonamides from the corresponding iodides. Tetrahedron Lett. 2011,52 (7), 820-823.

23.Ball, J. C.; Brennan, P.; Elsunaki, T. M.; Jaunet, A.; Jones, S., A tandem asymmetric synthesis approach for the efficient preparation of enantiomerically pure 9-(hydroxyethyl) anthracene. Tetrahedron: Asymmetry 2011,22 (3), 253-255.

References

Professor Chas Bountra

Chief Scientist (SGC) and Professor of Translational Medicine (Nuffield Department of Medicine)

University of Oxford

Professor Sir Peter Ratcliffe, FRS

Nuffield Professor of Medicine and Head of Nuffield Department of Medicine

University of Oxford

Professor Chris Schofield, FRS

Head of Organic Chemistry

University of Oxford

Professor Julian Blagg

Deputy Director

Cancer Research UK Cancer Therapeutics Unit

The Institute of Cancer Research