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Dr Helen Sheldrake

PositionLecturer in Organic and Medicinal Chemistry
DepartmentInstitute of Cancer Therapeutics
Telephone+44 (0) 1274 236858
EmailH.Sheldrake@bradford.ac.uk
LinkedInVisit my LinkedIn profile

Research Interests (key words only)

Dual/multi-integrin antagonism ; Synthesis of bioactive natural products ; New synthetic methods

Teaching and Supervisory Responsibilities

Course Leader: MSc Cancer Pharmacology

Module Leader: CLS3003-B Chemistry for Clinical Sciences, INC7017-B Critical Appraisal

Lecturer:

  • INC6001-B Fundamentals of Drug Discovery
  • INC7017-B Principles of Drug Discovery
  • INC7016-B Chemical Toolbox for Drug Discovery
  • INC7017-B Critical Appraisal
  • INC7001-B Predictive Models for Drug Evaluation
  • CLS4008-B and CLS6003-D Special Studies
  • INC7018-B Practical Skills in Research
  • Research projects supervisor

Supporting Student PPD: Personal tutor Clinical Sciences years 0-3, Cancer Pharmacology

Administrative Responsibilities

  • Cancer Therapeutics and Molecular Pharmacology seminar organiser
  • Chief departmental first aider
  • School Athena Swan Self-assessment Team

Study History

  • 2015: Fellow of the Higher Education Academy
  • 2001 - 2004: PhD, University of Cambridge
  • 1997 - 2001: MSci, St Catharine’s College, University of Cambridge

Professional History

2007-2014: RCUK Academic Fellow in Medicinal Chemistry, University of Bradford
2004-2007: Postdoctoral Research Associate, The University of Manchester

Research Areas

Postgraduate Student Supervision

  • Amal Elsharif (co-supervised with Dr Steve Shnyder and Prof LH Patterson): PhD project: Investigation of novel integrin antagonists in cancer models

Previous Group Members

  • Adam Throup: PhD project: Development of activation specific integrin antagonists as enhanced anticancer therapeutics
  • Hanadi Ahmedah (co-supervised with Dr Steve Shnyder and Prof L H Patterson): PhD project: Investigation of the expression and function of αv, α5, and β5 integrins in cancers
  • Manar Zraikat (co-supervised with Dr Steve Shnyder, Dr Roger Phillips and Prof L H Patterson): PhD project: Development of in vitro models of invasion for pharmacological investigation of small molecule inhibitors of tumour progression
  • Fatemah Al-Shammari (co-supervised with Dr Steve Shnyder and Prof LH Patterson): PhD project: Investigations of beta3 Integrin expression and inhibition in tumours
  • Ana-Rita Neves Dos Santos (co-supervised with Dr Klaus Pors): PhD Project: Development of new methodologies to synthesise biologically active tetrahydroisoquinolines
  • Andrew Gordon (Research Assistant funded by The Prostate Cancer Charity) A new treatment for castration resistant prostate cancer

Integrin Antagonists as Modulators of Tumour Progression and Dissemination

The integrin family of transmembrane receptors mediate cell-cell and cell-extracellular matrix interactions and a wide range of cell signalling pathways; changes in integrin expression are frequently seen in cancer.  The RGD-binding integrins are particularly relevant to cancer metastasis.  Abnormal expression and activation of aIIbß3 and avß3 in tumours is associated with aggressive disease, metastasis and poor prognosis and microenvironment-mediated drug resistance.  There is potential for dual-antagonism of aIIbß3 and avß3  in cancer treatment; ß3 dual antagonists can prevent tumour invasion by several pathways, blocking the interaction between tumour cells and platelets, or between ß3-expressing tumour cells and ECM in addition to interfering with altered cell signalling pathways resulting in superior efficacy to singly-targeted agents.  Identification of other integrin combinations will provide personalised therapy targeted to specific tumour types.

Using rational design supported by molecular modelling, we have identified novel structures to create a new class of agent with potential as high affinity selective dual integrin antagonists. We are working with Dr Mark Sutherland and Dr Steve Shnyder to progress these compounds to preclinical development as potential treatments for melanoma and prostate cancer.

Design and synthesis of chloromethylindolines with a tumour-selective bio-oxidative mode of activation (in collaboration with Dr Klaus Pors)

Part of our work on target directed methodology and synthesis involves developing new routes to synthesis of chloromethylindolines such as duocarmycin SA.

Synthesis of bioactive natural products

Current targets of interest include nigramide Q, providencin, cochlioquinolines.

Research Collaborations

  • Prof Alan Melcher, Dr Maria Marples, St James's Hospital, Leeds (integrin project)
  • Dr Darren Tomlinson, University of Leeds (anti-integrin adhirons)
  • Dr. Hanadi Talal Ahmedah, College of Health and Rehabilitation Sciences, Princess Nourah Bint Abdulrahman University, Saudi Arabia

Publications

Publications are available at Bradford Scholars from the link here

  • Throup A, Patterson LH, Sheldrake HM. Intramolecular thermal stepwise [2 + 2] cycloadditions: investigation of a stereoselective synthesis of [n.2.0]-bicyclolactones †Electronic supplementary information (ESI) available. Organic & Biomolecular Chemistry. 2016;14(40):9554-9559. Open Access www.ncbi.nlm.nih.gov/pmc/articles/PMC5066561/
  • M. J. Stephenson, L. A. Howell, M. A. O'Connell, K. R. Fox, C. Adcock, J. Kingston, H. Sheldrake, K. Pors, S. P. Collingwood, M. Searcey. The solid phase synthesis of duocarmycin analogues and the effect of C-terminal substitution on biological activity. J Org Chem. 2015, 80, 9454-9467
  • H. M. Sheldrake and L. H. Patterson. Strategies to inhibit tumor associated integrin receptors: rationale for dual and multi-antagonists. J. Med. Chem., 2014, 57, 6301-6315
  • H.M. Sheldrake, S. Travica, I. Johansson, P. Loadman, M. Sutherland, L. Elsalem, N. Illingworth, A. Cresswell, T. Reuillon, Tristan; S. Shnyder, S. Mkrtchian, M. Searcey, M. Sundberg, L. Patterson and K. Pors. Re-engineering of the Duocarmycin Structural Architecture Enables Bioprecursor Development Targeting CYP1A1 and CYP2W1 for Biological Activity. J. Med. Chem. 2013, 56, 6273-6277
  • S. Travica, K. Pors, P. M. Loadman, S. D. Shnyder, I. Johansson, M. N. Alandas, H. M. Sheldrake, S. Mkrtchian, L. H. Patterson, and M. Ingelman-Sundberg. Colon cancer-specific cytochrome P450 2W1 converts duocarmycin analogues into potent tumor cytotoxins. Clin. Cancer Res. 2013, 19, 2952-2961
  • M. Sutherland, P. Loadman, J. H. Gill, J. P. Laye, H. M. Sheldrake, N. Illingworth, M. N. Alandas, P. A. Cooper, M. Searcey, K. Pors, S. D. Shnyder, and L. H. Patterson. Antitumor activity of a duocarmycin analogue rationalised to be metabolically activated by cytochrome P450 1A1 in human transitional cell carcinoma of the bladder. Mol. Cancer Ther. 2013, 12, 27-37
  • M. Sutherland, P. Loadman, J. H. Gill, J. P. Laye, H. M. Sheldrake, N. Illingworth, M. N. Alandas, P. A. Cooper, M. Searcey, K. Pors, S. D. Shnyder, and L. H. Patterson. Antitumor activity of a duocarmycin analogue rationalised to be metabolically activated by cytochrome P450 1A1 in human transitional cell carcinoma of the bladder. Mol. Cancer Ther. 2013, 12, 27-37
  • M. Sutherland, A. Gordon, S. D. Shnyder, L. H. Patterson and H. M. Sheldrake. RGD-binding integrins in prostate cancer: expression patterns and therapeutic prospects against bone metastasis. Cancers, 2012, 4, 1106-1145. (Open access: go to http://www.mdpi.com/2072-6694/4/4/1106 to read this review)
  • 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. Modification of the duocarmycin pharmacophore enables CYP1A1 targeting for biological activity, Chem Commun.,2011, 47, 12062-12064
  • Sheldrake, H.M., Patterson, L.H., "Function and Antagonism of beta 3 integrins in the development of cancer therapy," Curr Cancer Drug Targets, 2009, 9, 519-540
  • Sheldrake, H.M., Jamieson,C., Pascu, S.I., and Burton, J.W., Synthesis of the originally proposed structure of elatenyne and an enyne from Laurencia majuscula, Org. Biomol. Chem., 2009, 7, 238-252
  • Pritchard, R.G., Sheldrake, H.M., Taylor, I.Z., and Wallace, T.W., "Rapid stereoselective access to the tetracyle core of puupehenone and related sponge metabolites using metal-free radical cyclisations of cyclohexenyl-substituted 3-bromochroman-4-ones," Tetrahedron Lett, 2008, 49, 4156-4159
  • Sheldrake, H.M., Wallace, T.W., and Wilson, C.P., "Functionalised Cyclobutenes via Multicomponent Thermal [2+2] Cycloaddition Reactions", Org. Lett., 2005, 7, 4233-4236

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