Dr David France (Chemistry, University of Glasgow) http://www.gla.ac.uk/schools/chemistry/staff/davidfrance/
Dr Justin Bower (Drug Discovery, CRUK Beatson Institute)
Prof Laura Machesky (CRUK Beatson Institute)
The standard model for drug therapy relies on a 1:1 correlation between a drug molecule and its biomolecular target. Drug dosing regimens must take this requirement into account. This is a particular challenge for cancer therapy where distinguishing between cancer cells and healthy cells is essential to avoid toxic side effects. An emerging strategy in Medicinal Chemistry called “Protac” attempts to overcome the requirement for a 1:1 correspondence between drugs and their targets. This is achieved through the selective degradation of multiple copies of a target protein by a single Protac molecule. The consequent ability to use low drug doses has the potential to lead to new cancer therapies with minimal toxic side effects. This project will examine the Protac approach in the context of the actin bundling protein Fascin. Fascin is a uniquely good therapeutic target because it is not expressed in most normal epithelial tissues, but is strongly upregulated during multiple tumour progression programmes, including in pancreatic cancer, breast cancer and colorectal cancers. The student will work with experts in multiple disciplines including chemical synthesis of the Protac molecules, structural biology to design compounds with optimized binding, and cellular invasion assays to determine efficacy. Ultimately, this project aims to validate the Protac approach to preventing cancer invasion and metastasis by degradation of Fascin.
Keywords: Protac, Protein degradation, Cell migration and invasion, Cancer metastasis, Pancreatic cancer
France, DJ, G Stepek, DR Houston, L Williams, G McCormack, MD Walkinshaw, and AP Page. 2015. Identification and activity of inhibitors of the essential nematode-specific metalloprotease DPY-31. Bioorganic and Medicinal Chemistry Letters 25:5752-5.
Smith, CD, and DJ France. 2014. 2-Alkenyl Furans from a Palladium-Catalyzed Cyclization and Coupling of Ene- Yne-Ketones. ChemCatChem 6:711-12.
Hewitt, JFM, L Williams, P Aggarwal, CD Smith, and DJ France. 2013. Palladium-Catalyzed Heteroallylation of Unactivated Alkenes – Synthesis of Citalopram. Chemical Science 4:3538-43.
Canham, SM, DJ France, and LE Overman. 2013. Total Synthesis of (+)-Sieboldine A: Evolution of a Pinacol- Terminated Cyclization Strategy. Journal of Organic Chemistry 78:9-34.
Oelke, AJ, F Antonietti, L Bertone, PB Cranwell, DJ France, RJM Goss, T Hofmann, S Knauer, SJ Moss, PC Skelton, RM Turner, G Wuitschik, and SV Ley. 2011. Total Synthesis of Chloptosin: A Dimeric Cyclohexapeptide Chemistry a European Journal 17:4183-94.
Bower, JF, Pugliese, A and Drysdale, MJ. 2016. Strategies for Fragment Library Design. Fragment-based Drug Discovery Lessons and Outlook, Wiley-VCH 99-118
Bilsland, AE, Pugliese, A, Liu, Y, Revie, J, Burns, S, McCormick, C, Cairney, CJ, Bower, J, Drysdale, M, Narita, M, Sadaie, M and Keith, N. 2015. Identification of a Selective G1-Phase Benzimidazolone Inhibitor by a Senescence-Targeted Virtual Screen Uisng Artificial Neural Networks. Neoplasia 9:704-715.
Unbekandt, M, Croft, DR, Crighton, D, Mezna, M, McArthur, D, McConnell, P, Schuttelkopf, AW, Belshaw, S, Pannifer, A, Sime, M, Bower, J, Drysdale, M and Olson, MF. 2014. A Novel Small-Molecule MRCK Inhibitor Blocks Cancer Cell Invasion. Cell Communication and Signaling 12:54.
Czyzewski, M, Sellars, JD, Guliashvili, T, Tibbelin, J, Johnstone, L, Bower, J, Box, M, Ottosson, H, Steel, PG. 2014. The First Intramolecular Silene Diels-Alder Reactions. Chemical Communications 50:2919-2921.
Morley, A, Bower, JF, Pugliese, A, Birchall, K, Brennan, P, Brown, N, Chapman, T, Jordan, AJ, Hoelder, S, Ley, SV, Drysdale, M, Miller, D, Swarbrick, M, Gilbert, I and Wyatt, P. 2013. Fragment-based Hit Identification: Thinking in 3D, Drug Discovery Today 18:1221-1227.
Tyrrell BJ, Woodham EF, Spence HJ, Strathdee D, Insall RH, Machesky LM. Loss of strumpellin in the melanocytic lineage impairs the WASH Complex but does not affect coat colour. Pigment Cell Melanoma Res. 2016 Sep;29(5):559-71.
García E, Ragazzini C, Yu X, Cuesta-García E, Bernardino de la Serna J, Zech T, Sarrió D, Machesky LM, Antón IM. WIP and WICH/WIRE co-ordinately control invadopodium formation and maturation in human breast cancer cell invasion. Sci Rep. 2016 Mar 24;6:23590.
Ma Y, Faller WJ, Sansom OJ, Brown ER, Doig TN, Melton DW, Machesky LM. Fascin expression is increased in metastatic lesions but does not correlate with progression nor outcome in melanoma. Melanoma Res. 2015 Apr;25(2):169-72.
Ma Y, Machesky LM. Fascin1 in carcinomas: Its regulation and prognostic value. Int J Cancer. 2015 Dec 1;137(11):2534-44.
Li A, Morton JP, Ma Y, Karim SA, Zhou Y, Faller WJ, Woodham EF, Morris HT, Stevenson RP, Juin A, Jamieson NB, MacKay CJ, Carter CR, Leung HY, Yamashiro S, Blyth K, Sansom OJ, Machesky LM. Fascin is regulated by slug, promotes progression of pancreatic cancer in mice, and is associated with patient outcomes. Gastroenterology. 2014 May;146(5):1386-96.e1-17. doi: 10.1053/j.gastro.2014.01.046.