Research

Drug discovery and development in the pharmaceutical industry

Drug discovery and development can be subdivided into three activities: understanding the disease process including the selection of pathway/molecular targets; development of candidate drugs with appropriate pharmacodynamics and pharmacokinetics; testing drugs in clinical trials. The majority of drug projects fail, at great cost, usually for a combination of factors related to these activities. Drug discovery research in the pharmaceutical industry is governed by the principles of discipline, process and business in order “to be practical and to play to the probabilities” (C. Lipinski, C. & E. News, Nov. 2007). Consequently, large pharma is optimally organized for mainstream research, but it offers a difficult environment for high-risk, long-term research which thrives best in academic laboratories.

Our Research

Research at the Institute of Pharmaceutical Sciences (IPW) is guided by the concept "Targets - therapeutics - diagnostics: From concepts to prototypes". The mission of our group at the IPW is to achieve drugability of RNA.

“Drugability” is a classification of structural elements in a target macromolecule which permits strong, selective interactions with drug-like molecules, leading to modulated biological activity. Intuitively, RNAs which fold into stable structures in order to dock regulatory RNAs and RNA binding proteins (RBPs) should be drugable and, in fact, Nature has evolved a variety of ligands - antibiotics and riboswitches - which modulate the function of certain RNAs with pharmacologically-useful activity. However, traditional medicinal chemistry approaches with RNA have consistently failed to develop useful small-molecule leads. Problems include: ligand-binding requires an energy-demanding displacement of water from the heavily-solvated, polyanionic RNA; a lack of means to target selectively RNA sequences using small ligands; no systematic means to identify biochemically-important functional sites within the target RNA structure.

It may never be possible to develop small-molecule ligands as drugs targeting RNA in the classical sense. However, beginning with the only effective ligands capable of targeting potently and specifically RNA - complementary oligonucleotides - there is much opportunity for innovation and progress.

We believe that advances in the drugability of RNA require activities in three areas:

• New chemical classes of RNA ligands which are as potent and selective as complementary oligonucleotides. Sporadic literature reports have suggested that the oligonucleotides can be shortened drastically and modified without excessively compromising potency and selectivity if they are directed to “privileged” binding sites on target RNA structures e.g. bulges. Applying state-of-the-art oligonucleotide synthesis techniques we have initiated projects to identify new classes of building blocks designed to exploit such binding sites. Our long term goal is to develop biologically-active ligands with a molecular weight below 2’000 Da.

• In vitro assays to characterize RNA-ligand interactions in order to understand and improve activity in vivo. To identify privileged binding sites on RNAs we have established a surface plasmon resonance (SPR)-based approach which permits the kinetics and thermodynamics of RNA-ligand interactions to be measured. Selected ligands are then assayed for biological activity in assays e.g. inhibitors of dicer processing, reporter systems and functional assays.

• Identification of coding and non-coding RNAs that play major roles in disease-associated pathways. We are exploring new approaches to identify RNA targets in disease-causing mechanisms. For example, we unraveled a previously unrecognized mechanism of resistance to tumor suppressive TGF-beta activity in cultured epithelial cell lines involving the regulation of latent TGF-beta processing factors by three oncomirs.

Our work is funded by the ETH Schulleitung, the IPW and with grants from the ETH, SNF, SNF – Sinergia and Krebsforschung Schweiz.

Key publications

Structural basis of pre-let-7 miRNA recognition by the zinc knuckles of pluripotency factor Lin28
F. E. Loughlin, L. F. R. Gebert, H. Towbin, A. Brunschweiger, J. Hall,  F. H-T. Allain.
Nature Structural & Molecular Biology (2012), 19, 84-89.

A Decade of the Human Genome Sequence----How Does the Medicinal Chemist Benefit.
A. Brunschweiger, J. Hall.
ChemMedChem (2012) in press.

Suppression of latent TGF-beta1 restores growth inhibitory TGF-beta signaling through microRNAs
A.M. Dogar, H. Towbin, J. Hall. Journal of Biological Chemistry (2011) 286, 16447-16458.
Identification of a regulatory feedback loop in which microRNAs play a key role in resistance to tumor-suppressive TGF-beta signaling.

J. Hall, P. Dennler, S. Haller, A. Pratsinis, K. Säuberli, H. Towbin, K. Walther, J. Woytschak. Genomics drugs in clinical trials.
Nature Reviews Drug Discovery (2010) 9, 988-989.
Arguments that contrary to current opinion concerning contributions of genomics to medicine, several drugs in clinical testing would likely not exist had it not been for genomics data in the discovery phases.

A novel microarray approach reveals new tissue-specific signatures of known and predicted mammalian microRNAs.
I. Beuvink, F.A. Kolb, W. Budach, A. Garnier, J. Lange, F. Natt, U. Dengler, J. Hall, W. Filipowicz, J. Weiler.
Nucleic Acids Research (2007) 35, e52 (approx. 50 citations).
Development of one of the first microarray platforms for microRNAs using a planar-wave guide surface and a data-comparison to the stem-loop PCR method.

Genome-wide functional analysis of human cell-cycle regulators.
M. Mukherji, R. Bell, L. Supekova, Y. Wang, A.P. Orth, S. Batalov, L. Miraglia, D. Huesken, J. Lange, C. Martin, S. Sahasrabudhe, M. Reinhardt, F. Natt, J. Hall, M. Labow, S.K. Chanda, C.Y. Cho, P.G. Schultz. 
Proceedings of the National Academy of Sciences, USA (2006) 103, 14819-14824 (approx. 50 citations).
One of the earliest whole-genome siRNA screens run at the Genomics Institute of the Novartis Research Foundation using the Novartis library.

Design of a genome-wide siRNA library using an artificial neural network.
D. Huesken, J. Lange, C. Mickanin, J. Weiler, F. Asselbergs, J. Warner, B. Meloon, S. Engel, A. Rosenberg, D. Cohen, M. Labow, M. Reinhardt, F. Natt, J. Hall. 
Nature Biotechnology (2005) 23, 995-1001 (>130 citations). Assembly of a whole genome library of siRNAs for genome screening.

siRNA relieves chronic neuropathic pain.
G. Dorn, S. Patel, G. Wotherspoon, M. Hemmings-Mieszczak, J. Barclay, F. Natt, P. Martin, S. Bevan, A. Fox, P. Ganju, W. Wishart, J. Hall.
Nucleic Acids Research (2004) 32, e49 (>200 Citations).
Use of antisense and RNAi in in vivo models of disease which resulted in one of the earliest accounts of the therapeutic effects of siRNAs in accepted models of neuropathic pain.