Molecular design approaches for the development of new anticancer drugs Alberto Del Rio The drug discovery pipeline Targets & Leads Target selection 12-24m Target to Lead 12-24m Drugs Lead to candida te 30-33m Candidate selection to FTIH 8-12m Products FTIH to PoC PoC to Commit Phase to Phase III III 12-44m 0-30m 18-66m File & Launch Lifecycl e mgt 10-13m 9 - 16 y PhI PhII PhIII Clinical PhIV GLP (Good Laboratory Practice) GCP (Good Clinical Practice) GMP(Good Manufacturing Practice) FDA/EMEA review 0.5-2 years Patents: Structure class, compound specific, synthesis, indication, formulation Patent time: • 20 years from the filing date • Drug development 10-14 years Costs ~ $1 billion per successful product 2 Small-molecule versus biologics sNME standard new molecular entities nTBS new therapeutic biologics Atorvastatin, marketed by Pfizer as a calcium salt under the trade name Lipitor Adalimumab, trade name Humira, is a TNF inhibiting anti-inflammatory drug Member of the drug class known as statins, used for lowering blood cholesterol First fully human monoclonal antibody drug approved by the FDA Best selling drug in pharmaceutical history, sales of Lipitor since it was approved in 1996 exceed US$125 billion In 2012 Humira drug had $4.3 billion of sales in the US and $9.3 billion worldwide Patent expired in 2012 3 Drug innovation – approved drugs Kneller, R. Nat. Rev. Drug Discov. 2010, 9, 867–82. 4 Attrition rate Arrowsmith, J.; Miller, P. Nat. Rev. Drug Discov. 2013, 12, 569 Beware of demonizing pharma industry! Drug company make lot of money, but they need to spend lot of money to guarantee development and sustainability 5 Medicinal chemistry 6 Computer-aided molecular design 7 Computer-aided molecular design Structural biology Biophysics Chemoinformatics Crystallography Homology modelling Molecular dynamics Docking ab initio protein modelling Protein-Protein docking Pharmacophore QSAR/QSPR NMR Database mining Modelling Similarity/Diversity Shape-screening Free energy estimation QM/MM CompChem MedChem OrgChem ADMETox Library design Combinatorial Chemistry Retrosynthetic analysis Synthetic Chemistry Biochemistry Molecular biology Cell biology Sanders, M. P. a, Barbosa, A. J. M., Zarzycka, B., Nicolaes, G. a F., Klomp, J. P. G., de Vlieg, J., and Del Rio, A. (2012), J Chem Inf Model, 52, 1607–1620. Barbosa, A. J. M., and Del Rio, A. (2012), Curr Top Med Chem 12, 866–77. Del Rio, A., Barbosa, A. J. M., Caporuscio, F., and Mangiatordi, G. F. (2010), Mol Biosyst 6, 2122–8. Medina-Franco, J. L., Martínez-Mayorga, K., Peppard, T. L., and Del Rio, A. (2012), PLoS ONE, 7, e50798. 8 A typical scenario of virtual screening Starting DB Million cmpds Selection & purchase Experimental difficulties Tens cmpds Not soluble Not permeable Not pure … Hit compounds Typical IC50 enzymatic assays determination Millimolar range Micromolar range Nanomolar range Sub-nanomolar range 0.1µM < IC50<100µM 1nM < IC50< 100nM IC50 < 1nM IC50>0.1mM Give up Not bad but … Have a beer ;) A miracle! 9 Targeting human Aromatase About 75% of breast cancers contain high level of oestrogens which enhance tumour-cell growth as a result of increased aromatase activity. First X-ray structure of Human Aromatase published in 2009 HTVS Caporuscio, F., Rastelli, G., Imbriano, C., and Del Rio, A. (2011), J Med Chem, 54, 4006–17. 10 Acknowledgments AIRC Start Up Regional Program Emilia Romagna Chemoinformatics Marijn Sanders (Radboud University Nijmegen) José L. Medina-Franco (Mayo Clinic, Scottsdale, AZ) Sirtuins Alessio Nencioni (Univ. of Genova) Santina Bruzzone Alessia Grozio Inga Bauer Enrico Millo Giovanna Sociali Proteasome and Immunoproteasome Claudio Franceschi (Univ. of Bologna) Elena Bellavista Dyskerin Lorenzo Montanaro (Univ. of Bologna) Argonaute Francesco Fazi (Univ. of Rome “La Sapienza”) Armenio JM Barbosa Federico Andreoli Marco Daniele Parenti Synthetic Chemistry Greta Varchi (ISOF, CNR, Bologna) Methyltransferases Cristiano Simone (Consorzio Mario Negri Sud) Aldo Germani Valeria Di Virgilio Alessia Peserico Paola Sanese Poly(ADP-ribose) Polymerases Maria Di Girolamo (Consorzio Mario Negri Sud) Hexokinases Renzo Cordera (Univ. of Genoa) Gianmario Sambuceti Davide Maggi Barbara Salani 13
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