One key goal of our work is to translate insights from fundamental research to improvements in the treatment of cancer. However, two major scientific challenges impede efforts to translate recent advances in our molecular understanding of cancer to new medicines for clinical application. First, many cellular processes that represent clinically validated opportunities for the treatment of cancer are mediated by macromolecular assemblies, such as protein-protein interactions, which, are not routinely accessible to conventional methods for the identification of chemical leads. This curtails the repertoire of ‘druggable’ targets for intervention using small molecules. Second, limitations in our understanding of the biological effects of new agents impede their early clinical development. This makes it difficult to select appropriate clinical indications and drug combinations during the transition from Phase I to Phase II clinical trials, leading to an unacceptably high attrition rate. We are developing a palette of new approaches to tackle these challenges, including new strategies to enlarge the ‘druggable’ target repertoire, to identify biomarkers for drug responsiveness, and to use this information in early-phase clinical trials.
Interdisciplinary approaches to extending the repertoire of ‘druggable’ targets.
This has led to strong collaborations with colleagues in physics (Payne), chemistry (Abell, Balasubramanian, Spring), biochemistry (Blundell,Hyvonen) and clinical medicine (Jodrell, Tuveson), besides pharma and biotech companies. We participate in the Cambridge Molecular Therapeutics Programme, a University-wide interdisciplinary initiative to pioneer approaches for the discovery and development of drugs against new types of molecular targets, as well as the Physics of Medicine programme.
These links support a range of ongoing projects in our laboratory that use interdisciplinary tools to investigate biological problems, and to create small molecules as tools for chemical biology and to seed the development of drugs.
Allosteric modulation of AURKA kinase activity by a small-molecule inhibitor of its protein-protein interaction with TPX2. Janeček M, Rossmann M, Sharma P, Emery A, Huggins DJ, Stockwell SR, Stokes JE, Tan YS, Almeida EG, Hardwick B, Narvaez AJ, Hyvönen M, Spring DR, McKenzie GJ, Venkitaraman AR. Sci Rep. 2016 Jun 24;6:28528.
Overcoming Chemical, Biological, and Computational Challenges in the Development of Inhibitors Targeting Protein-Protein Interactions.Laraia L, McKenzie G, Spring DR, Venkitaraman AR, Huggins DJ. Chem Biol (2015) Jun 18;22(6):689-703.
Diversity-oriented synthesis as a tool for identifying new modulators of mitosis.Ibbeson B.M., Laraia L., Alza E, O' Connor C.J., Tan Y., Davies H.M., McKenzie G., Venkitaraman A.R.*, Spring D.* Nature
Commun. (2014) 5:3155.
From crystal packing to molecular recognition: prediction and discovery of a binding site on the surface of polo-like kinase 1. Śledź P, Stubbs CJ, Lang S, Yang YQ, McKenzie GJ, Venkitaraman AR, Hyvönen M, Abell C. Angew Chem Int Ed Engl. 2011 Apr 18;50(17):4003-6.
Rational methods for the selection of diverse screening compounds. Huggins DJ, Venkitaraman AR, Spring DR. ACS Chem Biol. 2011 Mar 18;6(3):208-17.
G-quadruplex-binding benzo[a]phenoxazines down-regulate c-KIT expression in human gastric carcinoma cells. McLuckie KI, Waller ZA, Sanders DA, Alves D, Rodriguez R, Dash J, McKenzie GJ, Venkitaraman AR, Balasubramanian S. J Am Chem Soc. 2011 Mar 2;133(8):2658-63.
Context dependence of checkpoint kinase 1 as a therapeutic target for pancreatic cancers deficient in the BRCA2 tumor suppressor. Hattori H, Skoulidis F, Russell P, Venkitaraman AR. Mol Cancer Ther. 2011 Apr;10(4):670-8.
Germline Brca2 heterozygosity promotes Kras(G12D) -driven carcinogenesis in a murine model of familial pancreatic cancer. Skoulidis F, Cassidy LD, Pisupati V, Jonasson JG, Bjarnason H, Eyfjord JE, Karreth FA, Lim M, Barber LM, Clatworthy SA, Davies SE, Olive KP, Tuveson DA, Venkitaraman AR. Cancer Cell. 2010 Nov 16;18(5):499-509.
Computational analysis of phosphopeptide binding to the polo-box domain of the mitotic kinase PLK1 using molecular dynamics simulation. Huggins DJ, McKenzie GJ, Robinson DD, Narváez AJ, Hardwick B, Roberts-Thomson M, Venkitaraman AR, Grant GH, Payne MC. PLoS Comput Biol. 2010 Aug 12;6(8).
A conserved quadruplex motif located in a transcription activation site of the human c-kit oncogene. Fernando H, Reszka AP, Huppert J, Ladame S, Rankin S, Venkitaraman AR, Neidle S, Balasubramanian S. Biochemistry. 2006 Jun 27;45(25):7854-60.
Novel structural features of CDK inhibition revealed by an ab initio computational method combined with dynamic simulations. Heady L, Fernandez-Serra M, Mancera RL, Joyce S, Venkitaraman AR, Artacho E, Skylaris CK, Ciacchi LC, Payne MC. J Med Chem. 2006 Aug 24;49(17):5141-53.