Biography

PhD Positions

Click here for current PhD opportunities in PHA. But feel free to email me to discuss projects outside these areas and alternative sources of funding.

Mark Searcey is Chair of Medicinal Chemistry and Head of the Schools of Pharmacy and Chemistry at UEA. His previous positions were as Reader (2006) then Chair of Medicinal Chemistry (2010) and Director of Research in Pharmacy at UEA, Senior Lecturer at the School of Pharmacy, University of London (2000-2006), Assistant Professor and Research Associate at the Scripps Research Institute, La Jolla, California (1997-1999) and as a Research Scientist with the St Luke’s Institute of Cancer Research at University College Dublin, Ireland (1991-1996). His post-doctoral research position was with Gerry Gallacher and Keith Brocklehurst at the Faculty of Basic Medical Sciences, Queen Mary College, University of London on polyclonal catalytic antibodies (1989-1991). He obtained a BSc(Hons) in chemistry from Loughborough University (1985) and PhD with Barry Lee at the Hatfield Polytechnic (now the University of Hertfordshire, 1989).

Research is focussed on interesting targets for the development of new therapeutics with a particular interest in targeting DNA and protein-proteins interactions. The group uses both solution and solid phase synthesis to make compounds based upon natural products or purely from synthetic sources. Some highlights include: in 2007, in collaboration with Christine Cardin, we described a new mode of binding to DNA that targeted a four way junction called a Holliday Junction (HJ). In 2010, we showed that we could induce the formation of a HJ at room temperature, another first with potential applications in nanotechnology as well as therapeutics. In 2003, we carried out the first solid phase synthesis of the chlorofusin peptide, part of a natural product targeted at the p53/MDM2 interaction and followed it with the solid phase synthesis of a triostin A analogue that represented the most efficient synthesis of this DNA binding molecule to date. We are currently focussed on targeting protein-protein interactions and DNA targets in cancer and inflammation, alongside the synthesis of natural products targets such as simocyclinone.

Current Group

  • Dr Marco Cominetti
  • Dr Andrew Beekman (Funded by BBSRC)
  • Muayyad Al-Shinayyin (joint with Lesley Howell)
  • Oliver Cartwright (Funded by BBSRC and Novartis, joint with David Russell
  • Issa Jyamubandi (Part-time, funded by LGC, joint with Lesley Howell)
  • Zoe Goddard (Funded by PDT Norfolk and UEA, joint with David Russell)
  • Morwen Williams (joint with Manfred Bochmann)
  • Max Kappus (ERASMUS student)
  • Zeinab Barry (4th Year MChem Project Student)


Selected Publications

Anti-inflammatory effect of a cell penetrating peptide targeting the Nrf2/Keap1 interaction
Steel, R.; Cowan, J.; Payerne, E.; O’Connell, M. A.; Searcey, M.
ACS Med. Chem. Lett 2012
DOI: 10.1021/ml300041g

Synthesis of Small Molecules Targeting Multiple DNA Structures using Click Chemistry.
Howell LA, Bowater RA, O'Connell MA, Reszka AP, Neidle S, Searcey M.
ChemMedChem. 2012, 7, (5), 792–804
DOI: 10.1002/cmdc.201200060.

Modification of the duocarmycin pharmacophore enables CYP1A1 targeting for biological activity
Pors, K; Loadman, P. M.; Shnyder, S. D.; Sutherland, M.; Sheldrake, H. M.; Guino, M, Kiakos, K.; Hartley, J. A.; Searcey, M.; Patterson, L. H.
Chem. Commun. 2011, 47, 12062-12064
DOI: 10.1039/C1CC15638A

A Small Molecule that Induces Assembly of a Four Way DNA Junction at Low Temperature
Howell, L. A.; Waller, Z. A. E.; Bowater, R.; O’Connell, M. A.; Searcey, M.
Chem. Commun. 2011, 47, 8262-8264.
DOI: 10.1039/C1CC12922H

Highlighted Publications

See All

Waller, Z. A. E., Howell, L. A., Macdonald, C. J., O'Connell, M. A., Searcey, M.

(2014)

Identification and characterisation of a G-quadruplex forming sequence in the promoter region of nuclear factor (erythroid-derived 2)-like 2 (Nrf2),

in Biochemical and Biophysical Research Communications

447.

pp. 128-32

Full Text UEA Repository

(Article)

(Published)


Sheldrake, H. M., Travica, S., Johansson, I., Loadman, P. M., Sutherland, M., Elsalem, L., Illingworth, N., Cresswell, A. J., Reuillon, T., Shnyder, S. D., Mkrtchian, S., Searcey, M., Ingelman-sundberg, M., Patterson, L. H., Pors, K.

(2013)

Re-engineering of the Duocarmycin Structural Architecture Enables Bioprecursor Development Targeting CYP1A1 and CYP2W1 for Biological Activity,

in Journal of Medicinal Chemistry

56.

pp. 6273-6277

Full Text UEA Repository

(Article)

(Published)


Rackham, B. D., Howell, L. A., Round, A. N., Searcey, M.

(2013)

Non-covalent duplex to duplex crosslinking of DNA in solution revealed by single molecule force spectroscopy,

in Organic & Biomolecular Chemistry

11.

pp. 8340-8347

Full Text UEA Repository

(Article)

(Published)


All Publications

See Highlights
<- Page 1 of 4 ->

Steel, R. J., O'Connell, M. A., Searcey, M.

(2018)

Perfluoroarene-based peptide macrocycles that inhibit the Nrf2/Keap1 interaction,

in Bioorganic & Medicinal Chemistry Letters

Full Text UEA Repository

(Article)

(E-pub ahead of print)


Williams, M., Green, A. I., Fernandez-Cestau, J., Hughes, D. L., O'Connell, M. A., Searcey, M., Bertrand, B., Bochmann, M.

(2017)

(C^Npz^C)AuIII complexes of acyclic carbene ligands: synthesis and anticancer properties,

in Dalton Transactions

46

(39)

pp. 13397–13408

Full Text UEA Repository

(Article)

(Published)


Bertrand, B., Fernandez-Cestau, J., Angulo, J., Cominetti, M. M., Waller, Z. A., Searcey, M., O'Connell, M. A., Bochmann, M.

(2017)

Cytotoxicity of Pyrazine-Based Cyclometalated (C^Npz^C)Au(III) Carbene Complexes: Impact of the Nature of the Ancillary Ligand on the Biological Properties,

in Inorganic Chemistry

56

(10)

pp. 5728–5740

Full Text UEA Repository

(Article)

(Published)


Austin, M. J., Hearnshaw, S. J., Mitchenall, L. A., McDermott, P. J., Howell, L. A., Maxwell, A., Searcey, M.

(2016)

A natural product inspired fragment-based approach towards the development of novel anti-bacterial agents,

in MedChemComm

7

(7)

pp. 1387-1391

Full Text UEA Repository

(Article)

(Published)


Angulo, J., Goffin, S., Gandhi, D., Searcey, M., Howell, L.

(2016)

Unveiling the "Three Finger Pharmacophore" required for p53-MDM2 Inhibition by Saturation Transfer Difference NMR Initial Growth Rates Approach,

in Chemistry - A European Journal

22

(17)

pp. 5858-5862

Full Text UEA Repository

(Article)

(Published)


Cominetti, M., Goffin, S., Raffel, E., Turner, K., Ramoutar, J., O'Connell, M., Howell, L., Searcey, M.

(2015)

Identification of a new p53/MDM2 inhibitor motif inspired by studies of chlorofusin,

in Bioorganic & Medicinal Chemistry Letters

25

(21)

pp. 4878-4880

Full Text UEA Repository

(Article)

(Published)


Stephenson, M., Howell, L., O'Connell, M., Fox, K. R., Adcock, C., Kingston, J., Sheldrake, H., Pors, K., Collingwood, S., Searcey, M.

(2015)

Solid-phase synthesis of duocarmycin analogues and the effect of C-terminal substitution on biological activity,

in The Journal of Organic Chemistry

80

(19)

pp. 9454–9467

Full Text UEA Repository

(Article)

(Published)


Vinader, V., Sadiq, M., Sutherland, M., Huang, M., Loadman, P., Elsalem, L., Shnyder, S., Cui, H., Afarinkia, K., Searcey, M., Patterson, L., Pors, K.

(2015)

Probing cytochrome P450-mediated activation with a truncated azinomycin analogue,

in MedChemComm

6

pp. 187-191

Full Text UEA Repository

(Article)

(Published)


Waller, Z. A. E., Howell, L. A., Macdonald, C. J., O'Connell, M. A., Searcey, M.

(2014)

Identification and characterisation of a G-quadruplex forming sequence in the promoter region of nuclear factor (erythroid-derived 2)-like 2 (Nrf2),

in Biochemical and Biophysical Research Communications

447

(1)

pp. 128-32

Full Text UEA Repository

(Article)

(Published)


Sheldrake, H. M., Travica, S., Johansson, I., Loadman, P. M., Sutherland, M., Elsalem, L., Illingworth, N., Cresswell, A. J., Reuillon, T., Shnyder, S. D., Mkrtchian, S., Searcey, M., Ingelman-sundberg, M., Patterson, L. H., Pors, K.

(2013)

Re-engineering of the Duocarmycin Structural Architecture Enables Bioprecursor Development Targeting CYP1A1 and CYP2W1 for Biological Activity,

in Journal of Medicinal Chemistry

56

(15)

pp. 6273-6277

Full Text UEA Repository

(Article)

(Published)


Rackham, B. D., Howell, L. A., Round, A. N., Searcey, M.

(2013)

Non-covalent duplex to duplex crosslinking of DNA in solution revealed by single molecule force spectroscopy,

in Organic & Biomolecular Chemistry

11

(48)

pp. 8340-8347

Full Text UEA Repository

(Article)

(Published)


Marin, M., Rackham, B. D., Round, A. N., Howell, L. A., Russell, D. A., Searcey, M.

(2013)

A rapid screen for molecules that form duplex to duplex crosslinks in DNA,

in Chemical Communications

49

(80)

pp. 9113

Full Text UEA Repository

(Article)

(Published)


Sutherland, M., Gill, J. H., Loadman, P. M., Laye, J. P., Sheldrake, H. M., Illingworth, N. A., Alandas, M. N., Cooper, P. A., Searcey, M., Pors, K., Shnyder, S. D., Patterson, L. H.

(2013)

Antitumor activity of a duocarmycin analogue rationalized to be metabolically activated by cytochrome P450 1A1 in human transitional cell carcinoma of the bladder,

in Molecular Cancer Therapeutics

12

(1)

pp. 27-37

Full Text UEA Repository

(Article)

(Published)


Howell, L. A., Bowater, R. A., O'Connell, M. A., Reszka, A. P., Neidle, S., Searcey, M.

(2012)

Synthesis of Small Molecules Targeting Multiple DNA Structures using Click Chemistry,

in ChemMedChem

7

(5)

pp. 792-804

Full Text UEA Repository

(Article)

(Published)


Steel, R., Cowan, J., Payerne, E., O'Connell, M., Searcey, M.

(2012)

Anti-inflammatory effect of a cell penetrating peptide targeting the Nrf2/Keap1 interaction.,

in ACS Medicinal Chemistry Letters

3

pp. 407-410

Full Text UEA Repository

(Article)

(Published)


Howe, J. D., Payerne, E., Woon, E. C. Y., Marfo, S. A., Searcey, M., Gavrilovic, J.

(2011)

Screening novel small molecules for effects on cancer cell migration,

in International Journal of Experimental Pathology

92

(3)

pp. A27-A27

UEA Repository

(Article)

(Published)


Howell, L., Waller, Z., Bowater, R., O'Connell, M., Searcey, M.

(2011)

A small molecule that induces assembly of a four way DNA junction at low temperature,

in Chemical Communications

47

(29)

pp. 8262-8264

Full Text UEA Repository

(Article)

(Published)


Pors, K., Loadman, P., Shnyder, S., Sutherland, M., Sheldrake, H., Guino, M., Kiakos, K., Hartley, J., Searcey, M., Patterson, L.

(2011)

Modification of the duocarmycin pharmacophore enables CYP1A1 targeting for biological activity,

in Chemical Communications

47

(44)

pp. 12062-12064

Full Text UEA Repository

(Article)

(Published)


Howell, L., Gulam, R., Mueller, A., O'Connell, M., Searcey, M.

(2010)

Design and synthesis of threading intercalators to target DNA,

in Bioorganic & Medicinal Chemistry Letters

1

(20)

pp. 6956-6959

Full Text UEA Repository

(Article)

(Published)


Collingwood, S., Lock, R., Searcey, M.

(2009)

Optimizing drugs for local delivery,

in Drug News & Perspectives

22

(10)

pp. 627-634

Full Text UEA Repository

(Article)

(Published)


<- Page 1 of 4 ->

Key Research Interests

Targeting DNA

One of the main focuses of the laboratory is the targeting of DNA as a potential route to therapeutically useful molecules. Many clinically used antitumour agents depend on the disruption of nucleic acid associated processes to exert their effects. In the future, new agents that have lower side effects and are more focussed on single targets (either genes or structures) will be required and this is a subject of investigation. 

We are interested in both synthetic molecules and natural products and combine studies of synthesis, biophysical and biochemical properties. In 2006, in collaboration with Christine Cardin at Reading University, we disclosed the first structure of a molecule binding to the four-way Holliday junction through a novel mode of action.[1] In 2011, we followed this with the first molecule that can promote the assembly of the junction at room temperature.[2] This compound was derived from a click chemistry approach that led to a series of compounds that could bind to various DNA structures, from duplexes to G-quadruplexes via junctions.[3] 

Molecules that bind to double stranded DNA still have potential as antitumour agents. Almost 10 years ago, with Laurence Patterson of the Bradford Institute for Cancer Therapeutics, Searcey proposed that the duocarmycins, ultrapotent antitumour natural products, could be redesigned to become prodrugs that were activated by bio-oxidative processes in cancer cells.[4] Working with the Bradford team, we have demonstrated that this is indeed the case [5] and have shown that the prodrugs have antitumour activity in cells expressing cytochrome P450 enzymes [6].

References

[1] Angew. Chem. Int. Ed. Eng. 2007, 46, 3850-3854; [2] Chem. Commun. 2011, 47, 8262-8264; [3] ChemMedChem, 2012, 7, 792-804; [4] Current Medicinal Chemistry - Anticancer Agents 2004 4, 457-460; [5] Chem. Commun. 2011, 47, 12062-12064; [6] J. Med. Chem. 2013, 56, 6273-6277.

Targeting protein-protein interactions

Signalling pathways in cellular systems are excellent targets for drug design. The plethora of projects focussed on designing kinase inhibitors comes from this recognition and the progression of imatinib into the marketplace. Whereas kinases have a defined binding site, signalling can also take place through two protein surfaces coming together, a daunting prospect for the design of inhibitors but one which is coming to the fore in the design of new agents. In 2003, we described the first synthesis of the peptide structure of chlorofusin, a natural product that has been shown to inhibit the interaction between p53 and mdm2.[7] The peptide lacked inhibitory activity, as did a series of analogues [8] and later work showed that the full structure of the natural product is required for activity, although the stereochemistry of the azaphilone was relatively unimportant.[9] 

More recently, we have begun a collaboration with the O’Connell group at UEA to study the Nrf2/Keap1 interaction. Inhibition of this interaction has potential in cancer chemoprevention and in inflammation and in 2013, we disclosed the first cell penetrating peptide to activate Nrf2 through binding to Keap1.[10] We are currently investigating small molecules that may also have an effect. We have developed a number of in vitro and cell culture assays in house in order to do this. Ironically, Nrf2 upregulation may also be a problem in cancer and we are also investigating Nrf2 as a target for inhibition.

References

[7] Org. Lett. 2003, 5, 5051-5054; [8] J. Org. Chem. 2007, 72, 5146-5151; [9] Tetrahedron Lett. 2009 50, 3151-3153 (50th Anniversary issue.); [10] ACS Med. Chem. Lett. 2012, 3, 407-410.

Synthesis and natural products

At the centre of all of our projects is organic synthesis. We use both solid and solution phase methodologies to generate the structures that are of interest to us. Often, this may involve the development of routes to natural products in order to study structure-activity relationships. In 2005, following on from our successful solid phase synthesis of the chlorofusin peptide, we synthesised the triostin A analogue TANDEM via a route that also allowed us to generate water soluble analogues [11][12]. We are applying solid phase methodology to the synthesis of other natural products.

Heterocyclic chemistry sits at the heart of most of our DNA targeting, with routes to acridines and analogues via, amongst others, classical [3] and benzyne [13] click chemistry, well established. We are currently investigating DNA gyrase inhibitors via the development of flexible routes to coumarins and analogues.

References

[11] J. Org. Chem. 2005, 70, 7654-7661; [12] Biochemistry, 2008, 47, 7900-7906; [13] Bioorg. Med. Chem. Lett. 2009, 19, 5880-5883.

 

External Activities and Indicators of Esteem

Learned Societies

Fellow of the Royal Society of Chemistry and Chartered Chemist
Member of the American Chemical Society

Invited Reviews/Book chapters

Searcey M.; Patterson, L. H. Resistance in Cancer: A Target for Drug Discovery. Current Medicinal Chemistry - Anticancer Agents 2004 4, 457-460.

Searcey, M. Duocarmycins - Natures Prodrugs? Curr. Pharm. Des. 2002 8, 1375-1390.

Casely-Hayford, M.; Searcey, M. The Azinomycins. Discovery, Synthesis and DNA-Binding Studies in DNA and RNA Binders From Small Molecules to Drugs; Demeunynck, M.; Bailly, C.; Wilson, W. D., Eds.; Wiley-VCH Weinheim, 2002. pp676-696

Refereeing

Journal of the American Chemical Society, Journal of Organic Chemistry, Journal of Medicinal Chemistry, Organic Letters, Biochemistry, Nucleic Acids Research, Organic and Biomolecular Chemistry, Chemical Communications, Bioorganic Medicinal Chemistry Letters, Bioorganic Medicinal Chemistry, International Journal of Pharmaceutics.

External Activities

Member of F1000 Biology

Member of the EPSRC Peer Review College.
Reviewer for BBSRC

Invited Talks

2014              School fo Chemistry, University of Reading

2013              Loughborough University School of Chemistry

2012              Medway School of Pharmacy.

2012              Strathclyde Institute for Biological and Pharmaceutical Sciences

2011              8th International Congress of Pharmaceutical Sciences, Brazil

2011              Brazilian Colloquium on Medicinal Chemistry

2011              Kings College London

2009              National Cancer Research Meeting, Birmingham, UK.

2009              Invited lecturer, Chemistry Department, University College London.

2008              RICT Meeting in Angers, France.

2008              1st Meeting on drug Discovery and Development, Dubai, UAE

2008              Invited Lecturer, University of Bergen, Norway.


PhD students

Twelve PhD students have graduated from the lab to date.

External Examiner

2017-2020      External examiner for MPharm, School of Pharmacy, Queens University of Belfast

2014-2017      External examiner for MSc in Drug Discovery, School of Pharmacy, Nottingham University.

2012-2016      External examiner for MSc in Chemical Sciences, Loughborough University.

2008-2011      External Examiner for Medicinal Chemistry on the Pharmacy degree at the Royal College of Surgeons in Ireland

2010-2013      External Examiner for medicinal chemistry, Welsh School of Pharmacy, CardiffUniversity.

2010-2011      External Examiner for MSc in Drug Discovery. University of Bradford.

2012-2015         External Examiner for Medicinal Chemistry for School of Pharmacy, University of Hertfordshire

I have acted as both internal and external examiner for around 23 PhD theses, 1 MPhil and 1 MSc.


Conference Organisation

2011 September - Society for Medicines Research Meeting, joint organiser, speaker and chair

2009 June - Society for Medicines Research Meeting, joint organiser and Chair
2006 March - Society for Medicines Research Cancer Treatments for the New Millennium Joint Organiser and Chair
2006 Sept - British Pharmaceutical Conference Joint Organiser RSC/RPSGB Medicinal Chemistry Symposium
2005 Sept - British Pharmaceutical Conference, Joint Organiser, Chair and Speaker.
2005 Oct - RSC Awards conference for Laurence Hurley and Bill Denny, Joint Organiser and Speaker
2005 July - RSC Nucleic Acids Forum of the Nucleic Acids Group. Organiser
2005 July - RSC Chilterns and Middlesex Postgraduate Symposum. Organiser.
2003 Sept - British Pharmaceutical Conference Chair and organiser of Medicinal Chemistry session