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.

 

Overview

 

The Drug Discovery Unit (DDU) integrates medicinal, computational and synthetic chemistry with advanced biochemical and biophysical assays, in vitro cellular biology and in vivo capability to develop novel and first in class therapeutics for the treatment of unmet needs in cancer patients. 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, and a track record of bringing projects from target validation to the clinic. The DDU builds upon fundamental biology discoveries made within the CRUK Manchester Institute to investigate novel drug discovery targets and to provide new chemical entities for the treatment of cancer.

 

Despite the impact of the coronavirus pandemic during the past year, research and laboratory work has continued apace during 2021, in a COVID-safe manner. We have strengthened our collaboration with colleagues in the CRUK Manchester Institute, and are working closely with Prof Iain Hagan, Prof Richard Marais and Dr Claus Jorgensen to advance drug discovery efforts against exciting targets involved in cancer cell cycle, in cancer cell stemness and resistance and in tumour stroma regulation, as well as progressing our suicide gene therapy for the treatment of solid tumours. We have actively sought to integrate our projects with Caroline Dive’s biomarker discovery programme wherever possible, so that all nominated targets have selection and predictive biomarkers. We have fostered close collaborations with our clinical colleagues at the Christie NHS Foundation Trust on a number of late stage projects.

 

Figure 1. The iterative cycle of drug discovery

 

Research highlights of 2021 include new promising results with our lysyl oxidase (LOX) inhibitors in models of pulmonary fibrosis and metastasis, and the discovery and biological assessment of very potent, selective and bioavailable inhibitors of several collaborative cancer targets which are advancing towards or through lead optimisation.

 

In 2021 two of our late stage projects, the RAF+SRC inhibitor 3833 and the LOX inhibitors, were selected from nearly 90 submissions by the Alderley Park Oncology Development Programme, a national programme designed to develop and progress start-up oncology projects. The programme, funded by Innovate UK and CRUK and backed by a consortium of global pharmaceutical and healthcare companies, aims to identify exciting oncology innovations that will improve the diagnosis and treatment of cancer and to help accelerate their progression towards commercialisation. Both our RAF+SRC and LOX projects reached the final stage of the programme as part of a select group of only six projects from the whole of the UK.

 

RAS-driven cancers such as pancreatic ductal adenocarcinoma (PDAC), colorectal carcinoma (CRC) and non-small cell lung cancer (NSCLC) account for about one third of human cancers. Despite over 40 years of research, most RAS-driven cancers remain areas of unmet clinical need and patients with these cancers still generally receive conventional chemotherapy – often with limited efficacy and potentially high toxicity. Multiple signalling pathways are activated in KRAS-mutant cancers, and blocking only one target or one pathway is often ineffective or has paradoxical consequences. For example, drugs targeting mutant BRAF cause KRAS-mutant tumours to grow, because KRAS uses another RAF pathway protein, CRAF, instead of BRAF, to signal. In addition, RAS-mutant cells also require SRC, a controller protein for multiple parallel signalling pathways, to signal cells to proliferate.

 

Figure 2:

 

The joint teams of Prof Springer and Prof Marais discovered 3833, an oral inhibitor for RAS-driven cancers with a unique mechanism of action as a bi-nodal RAF (BRAF and CRAF) + SRC inhibitor that targets these two key signalling pathways and so is effective in both BRAF-mutant and KRAS-mutant cancers (Figure 2A). A Phase I clinical trial (NCT02437227) at the Christie and Royal Marsden NHS Foundation Trusts, has shown that 3833 is well-tolerated by patients, with evidence of responses. 3833 significantly prolonged progression-free survival and partial response in a patient with a KRAS-driven spindle cell sarcoma who did not respond to the third-generation kinase inhibitor ponatinib and therefore had limited treatment options. This project was selected for the drug development programme at Alderley Park, with the aim of accelerating its progression to Phase II clinical trial and a subsequent route to approval.

 

Lysyl oxidases (LOX/LOXL1-4) crosslink collagens and elastin, stiffening the extracellular matrix (ECM). In collaboration with Prof Marais, we have discovered LOX and LOX family inhibitors with good pharmacological and pharmacokinetic properties. Our inhibitors have been designed to prevent the crosslinking of the ECM, which is a key step in the progression of pulmonary fibrosis, a disease that severely affects the quality of life of large numbers of patients. LOX also has important roles in the progression of tumour metastasis, which is the major cause of death in cancer patients. LOX inhibitors address large unmet needs as there is currently no effective therapeutic option for cancer metastasis and pulmonary fibrosis. We have already demonstrated therapeutic activity in primary tumour models of CRC, PDAC and breast cancer as well as anti-metastatic efficacy in preclinical models. New data in the bleomycin-induced model of pulmonary fibrosis have shown a marked reduction of positron-emmision tomography (PET) marker of fibrosis upon treatment with our LOX inhibitors (Figure 3). This is the second project selected by the Alderley Park Oncology Development Programme to be supported towards accelerating selection of a candidate drug to progress to toxicology and preclinical development studies before moving into early clinical trials in patients, as monotherapy and in combinations.

 

Figure 3:

 

We have continued our collaboration with IDEAYA Bioscience and with Stephen Taylor at The University of Manchester on in vivo model assessment for our Poly(ADP-ribose) glycohydrolase (PARG) inhibitors, for the treatment of ovarian, gastric and breast cancer. IDEAYA Bioscience is planning to file an IND by Q4 2022.

 

The DDU has a healthy portfolio of advanced small molecule inhibitors and biologics projects that are in lead identification, lead optimisation or later stages (Figure 4). The exciting potential of many of our projects has raised great commercial interest and we are looking to accelerate the progress of these projects with commercial funding.

 

Figure 4: Drug Discovery Unit portfolio of projects.

 

Selected Publications


Brown M, Aljarah M, Asiki H, Leung LMH, Smithen DA, Miller N, Nemeth G, Davies L, Niculescu-Duvaz D, Zambon A, Springer C. (2021)
Toward the Scale-Up of a Bicyclic Homopiperazine via Schmidt Rearrangement and Photochemical Oxaziridine Rearrangement in Continuous-Flow.
Organic Process Research & Development 25(1):148-156. PubMed abstract (PMID: 33679122) 

Saturno G, Lopes F, Niculescu-Duvaz I, Niculescu-Duvaz D, Zambon A, Davies L, Johnson L, Preece N, Lee R, Viros A, Holovanchuk D, Pedersen M, McLeary R, Lorigan P, Dhomen N, Fisher C, Banerji U, Dean E, Krebs MG, Gore M, Larkin J, Marais R, Springer C. (2021)
The paradox-breaking panRAF plus SRC family kinase inhibitor, CCT3833, is effective in mutant KRAS-driven cancers.
Annals of Oncology 32(2):269-278. PubMed abstract (PMID: 33130216)

Smithen DA, Leung LMH, Challinor M, Lawrence R, Tang H, Niculescu-Duvaz D, Pearce SP, Mcleary R, ​Lopes F, Aljarah M, Brown M, Johnson L, Thomson G, Marais R, Springer C. (2020)
2-Aminomethylene-5-sulfonylthiazole Inhibitors of Lysyl Oxidase (LOX) and LOXL2 Show Significant Efficacy in Delaying Tumor Growth. 
J Med Chem. 63(5):2308-2324. PubMed abstract

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 62(12):5863-5884.  PubMed abstract

Tang H, Leung L, Saturno G, Viros A, Smith D, Di Leva G, Morrison E, Niculescu-Duvaz D, Lopes F, Johnson L, Dhomen N, Springer C, Marais R. (2017)
Lysyl oxidase drives tumour progression by trapping EGF receptors at the cell surface.
Nature Communications 8:14909. 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

Girotti MR, Lopes F, Preece N, Niculescu-Duvaz D, Zambon A, Davies L, Whittaker S, Saturno G, Viros A, Pedersen M, Suijkerbuijk BM, Menard D, McLeary R, Johnson L, Fish L, Ejiama S, Sanchez-Laorden B, Hohloch J, Carragher N, Macleod K, Ashton G, Marusiak AA, Fusi A, Brognard J, Frame M, Lorigan P, Marais R, Springer C. (2015)
Paradox-breaking RAF inhibitors that also target SRC are effective in drug-resistant BRAF mutant melanoma.
Cancer Cell 27(1):85-96. PubMed abstract

Girotti MR, Pedersen M, Sanchez-Laorden B, Viros A, Turajlic S, Niculescu-Duvaz D, Zambon A, Sinclair J, Hayes A, Gore M, Lorigan P, Springer C, Larkin J, Jorgensen C, Marais R. (2013)
Inhibiting EGF receptor or SRC family kinase signaling overcomes BRAF inhibitor resistance in melanoma.
Cancer Discovery 3(2):158-67. PubMed abstract

 

 

 

 

Team

  • Head of Biology
  • Graeme Thomson
  • Bioscientists
  • Diana Baxter
  • Jessica Walker
  • Joanna Grabarek
  • ​Julia Morris
  • David Waterhouse
  • Head of Chemistry
  • Dan Niculescu-Duvaz
  • Chemists
  • Ali Raoof
  • Christopher Kershaw
  • Deborah Smithen
  • Efthymios-Spyridon Gavriil
  • Leo Man Ho Leung
  • Michael Brown
  • Mohammed Aljarah
  • James Norris
  • Computational Chemistry & Structural Biology
  • Christopher Fitzpatrick
  • Jennifer Miles
  • Graduate Students
  • James Stratford
  • Megan Mylrea
  • Mihaela Ficu
  • Executive Assistant
  • Jayne Fowler

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