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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.

 
Symmetrical dimer of (R132H) IDH1 in an “open”
conformation,5 with compound 9 (green carbons)
and the NADP cofactor (blue carbons) bound in
both subunits (PDB accession code 5L58)

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

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

Harris WJ, Huang X, Lynch JT, Spencer GJ, Hitchin JR, Li Y, Ciceri F, Blaser JG, Greystoke BF, Jordan AM, Miller CJ, Ogilvie DJ, Somervaille TC.
(2012)
The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells.
Cancer Cell 21(4):451. PubMed abstract

Hamilton NM, Dawson M, Fairweather E, Hamilton NS, Hitchin JR, James DI, Jones SD, Jordan AM, Lyons AJ, Small HF, Thomson GJ, Waddell ID, Ogilvie DJ. (2012)
Novel steroid inhibitors of glucose-6-phosphate dehydrogenase.
Journal of Medicinal Chemistry 55(9):4431-45. PubMed abstract

 

Team

Head of Chemistry
Allan Jordan

Chemists
Mohammed Aljarah
Michael Brown
Vikki Clayton
Mark Dodsworth
Laura Johnson
Chris Kershaw
Leo Leung
Rebecca Newton
Dan Niculescu-Duvaz
Ali Raoof
Kate Smith
Deborah Smithen

Bioscientists
Alex Baker
Habiba Begum
Elizabeth Blaikley
Charlotte Burt
Andrew Clifton
Cath Eberlein
Samantha Fritzl
Joanna Grabarek
Louise Griffiths
Nicola Hamilton
Ben Hodgson
Dominic James
Paul Kelly
Filipa Lopes
Nikki March
Robert McLeary
Alex Stowell
Graeme Thomson
Adnana Tudose
Graeme Walker

Graduate Students
Elizabeth Hogg

Undergraduate Students
Felix Rummel