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Drug Discovery - Caroline Springer

Professor Caroline Springer has led a team in cancer therapeutics for 25 years and has been involved in all stages of the drug discovery process in many different therapeutic areas. She completed her PhD in biological chemistry at University College London in 1984 and then moved to the Institute of Cancer Research, where in 1993 she established the Gene and Oncogene Targeting group. Over the last 25 years she also ran the development of various cancer treatments, including antibody, oncolytic viruses, metastases and cancer stem cell inhibitors. Her work has led to five clinical trials in antibody-directed and small molecule cancer therapies as well as nine preclinical candidate nominations and collaborations with pharmaceutical companies including AstraZeneca, Novartis and GSK. A key area of research has been to discover panRAF inhibitors for use in melanoma and colorectal cancers in collaboration with Institute Director Professor Richard Marais. She jointly led the development of new panRAF medicines that are currently undergoing clinical trials London and Manchester. Caroline is also working with Richard investigating lysyl oxidase inhibitors to prevent and treat metastases in a range of tumour types. A series of LOX inhibitors are now in late lead optimisation.

In October 2017, Caroline joined the CRUK Manchester Institute to become the new Director of the Drug Discovery Unit, superseding Donald Ogilvie who successfully led the DDU from its inception in 2009.

Introduction

Structural biology and docking.
Crystal structure of 3 bound to the catalytic
domain of human PARG (PDB entry 5LHB)

The Drug Discovery Unit builds upon fundamental biology discoveries made within the CRUK Manchester Institute, the Manchester Cancer Research Centre, The University of Manchester and the wider cancer research community. Integrating medicinal, computational and synthetic chemistry with in vitro and cellular biology, the centre investigates novel drug discovery targets in an attempt to provide new chemical entities for the treatment of unmet clinical needs in cancer patients.

 
Lysyl oxidase (LOX) cross-links collagens and
is a key driver of cancer growth and metastasis.
An aminomethylene inhibitor is shown targeting
LOX which results in breaks in the collagen cross-links,
as shown figuratively as the disintegrated spider's web
and targeting of the spider representing inhibition of
cancer and metastases. (Leung et al. JMedChem 62, 2019).

Initiated in early 2009, the principal aim of the Drug Discovery Unit is to deliver novel treatments into the clinical setting as efficiently as possible. We intend to bridge the translational gap between the fundamental biological research conducted both within the Institute and the wider University community, and the opportunities for clinical application afforded by our proximity to The Christie NHS Foundation Trust. Established as part of the Manchester Cancer Research Centre, the unit has established facilities to enable state-of-the-art biological and clinical target assessment and validation, small molecule drug design and synthesis and the biological evaluation of the resultant compounds.

The Drug Discovery Unit is now actively progressing a portfolio of small molecule projects against a variety of oncology targets.

Selected Publications

Leung L, Niculescu-Duvaz D, Smithen D, Lopes F, Callens C, McLeary R, Saturno G, Davies L, Aljarah M, Brown M, Johnson L, Zambon A, Chambers T, Ménard D, Bayliss N, Knight R, Fish L, Lawrence R, Challinor M, Tang H, Marais R, Springer C. (2019)
Anti-metastatic inhibitors of lysyl oxidase (LOX): design and structure-activity relationships.
Journal of Medicinal Chemistry [Epub 23 May 2019] PubMed abstract

Pillay N, Tighe A, Nelson L, Littler S, Coulson-Gilmer C, Bah N, Golder A, Bakker B, Spierings DCJ, James DI, Smith KM, Jordan AM, Morgan RD, Ogilvie DJ, Foijer F, Jackson DA, Taylor SS. (2019)
DNA Replication Vulnerabilities Render Ovarian Cancer Cells Sensitive to Poly(ADP-Ribose) Glycohydrolase Inhibitors.
Cancer Cell 35(3):519-533. PubMed abstract

Gogola E, Duarte AA, de Ruiter JR, Wiegant WW, Schmid JA, de Bruijn R, James DI, Guerrero Llobet S, Vis DJ, Annunziato S, van den Broek B, Barazas M, Kersbergen A, van de Ven M, Tarsounas M, Ogilvie DJ, van Vugt M, Wessels LFA, Bartkova J, Gromova I, Andújar-Sánchez M, Bartek J, Lopes M, van Attikum H, Borst P, Jonkers J, Rottenberg S. (2018)
Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality.
Cancer Cell 33(6):1078-1093. PubMed abstract

Mould DP, Bremberg U, Jordan AM, Geitmann M, McGonagle AE, Somervaille TCP, Spencer GJ, Ogilvie DJ. (2017)
Development and evaluation of 4-(pyrrolidin-3-yl)benzonitrile derivatives as inhibitors of lysine specific demethylase 1.
Bioorganic & Medicinal Chemistry Letters 27(20):4755-4759. PubMed abstract

Mould DP, Alli C, Bremberg U, Cartic S, Jordan AM, Geitmann M, Maiques-Diaz A, McGonagle AE, Somervaille TCP, Spencer GJ, Turlais F, Ogilvie D. (2017)
Development of (4-Cyanophenyl)glycine Derivatives as Reversible Inhibitors of Lysine Specific Demethylase 1.
Journal of Medicinal Chemistry 60(19):7984-7999. PubMed abstract

James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. (2016)
First-in-class chemical probes against poly(ADP-ribose) glycohydrolase (PARG) inhibit DNA repair with differential pharmacology to olaparib.
ACS Chemical Biology 11(11):3179-3190. PubMed abstract

Chapman PJ, James DI, Watson AJ, Hopkins GV, Waddell ID, Ogilvie DJ. (2016)
IncucyteDRC: An R package for the dose response analysis of live cell imaging data.
F1000Research 5:962. PubMed abstract

Newton R, Bowler KA, Burns EM, Chapman PJ, Fairweather EE, Fritzl SJ, Goldberg KM, Hamilton NM, Holt SV, Hopkins GV, Jones SD, Jordan AM, Lyons AJ, Nikki March H, McDonald NQ, Maguire LA, Mould DP, Purkiss AG, Small HF, Stowell AI, Thomson GJ, Waddell ID, Waszkowycz B, Watson AJ, Ogilvie DJ. (2016)
The discovery of 2-substituted phenol quinazolines as potent and selective RET kinase inhibitors with improved KDR selectivity.
European Journal of Medicinal Chemistry 112:20-32. PubMed abstract

Watson AJ, Hopkins GV, Hitchin S, Begum H, Jones S, Jordan A, Holt S, March HN, Newton R, Small H, Stowell A, Waddell ID, Waszkowycz B, Ogilvie DJ. (2016)
Identification of selective inhibitors of RET and comparison with current clinical candidates through development and validation of a robust screening cascade.
F1000Research 5:1005. PubMed abstract

Jordan AM, Waddell ID, Ogilvie DJ. (2015)
Rethinking ‘academic’ drug discovery: the Manchester Institute perspective.
Drug Discovery Today 20(5):525-35. PubMed abstract

Raoof A, Depledge P, Hamilton NM, Hamilton NS, Hitchin JR, Hopkins GV, Jordan AM, Maguire LA, McGonagle AE, Mould DP, Rushbrooke M, Small HF, Smith KM, Thomson GJ, Turlais F, Waddell ID, Waszkowycz B, Watson AJ, Ogilvie DJ. (2013)
Toxoflavins and deazaflavins as the first reported selective small molecule inhibitors of tyrosyl-DNA phosphodiesterase II.
Journal of Medicinal Chemistry 56(16):6352-70. PubMed abstract

 

Team

Head of Biochemistry
Graeme Thomson

Head of Cellular Pharmacology
Graeme Walker

Head of Medicinal Chemistry
Dan Niculescu-Duvaz

Head of Informatics & Modelling
Rae Lawrence

Lead Bioscientists
Alexandra Stowell
Andrew Clifton

Senior Bioscientists
Gareth Prosser
Mairi Challinor
Nicola Hamilton

Bioscientists
Emily Hannah Crowley
Joanna Grabarek

Lead Biologists
Robert Mcleary
Filipa Pereira Lopes

Senior Cell Biologists
Anna Tarafdar
Benjamin Hodgson
Elizabeth Blaikley
Sarah Brumskill

Cell Biologists
Alice Pilborough
Paul Kelly
Rebecca Holland

Principal Chemists
Deborah Smithen
Leo Man Ho Leung
Michael Brown
Mohammed Aljarah

Lead Chemists
Rebecca Newton
Ali Raoof

Senior Chemists
Christopher Kershaw
Ralph Kirk

Chemists
Paula Jackson
Cinzia Bordoni
Ephthymios Gavriil
Oleksandr Grytsai

Senior Computational Chemist
Christopher Fitzpatrick

Mathematician
Matthew Roberts

Graduate Students
Alex Anderton
Elizabeth Hogg
James Stratford
Megan Mylrea
Mihaela Ficu

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