WORLD CLASS BASIC, TRANSLATIONAL AND CLINICAL RESEARCH

Introduction

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.

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

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. (2020)
The paradox-breaking panRAF plus SRC family kinase inhibitor, CCT3833, is effective in mutant KRAS-driven cancers. 
Ann Oncol. S0923-7534(20)42986-2. PubMed abstract

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