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