HTS and hit finding in academia – from chemical genomics to drug discovery

The liaison between academia and the pharmaceutical industry was originally served primarily through the scientific literature and limited, specific industry–academia partnerships. Some of these partnerships have resulted in drugs on the market, such as Vorinostat (Memorial Sloan-Kettering Cancer Centre and Merck) and Tenofovir (University of Leuven; Institute of Organic Chemistry and Biochemistry, Czech Republic; and GlaxoSmithKline), but the timescales from concept to clinic have, in most cases, taken many decades. We now find ourselves in a world in which the edges between these sectors are more blurred and the establishment and acceptance of high-throughput screening alongside the wider concept of ‘hit discovery’ in academia provides one of the key platforms required to enable this sector to contribute directly to addressing unmet medical need.

[1]  Mark S Butler,et al.  The role of natural product chemistry in drug discovery. , 2004, Journal of natural products.

[2]  Adam Yasgar,et al.  Quantitative high-throughput screening: a titration-based approach that efficiently identifies biological activities in large chemical libraries. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[3]  A. Alberts,et al.  Discovery, biochemistry and biology of lovastatin. , 1988, The American journal of cardiology.

[4]  L. Mayr,et al.  Application of mass spectrometry technologies for the discovery of low-molecular weight modulators of enzymes and protein-protein interactions. , 2007, Current opinion in chemical biology.

[5]  Lorenz M Mayr,et al.  The Future of High-Throughput Screening , 2008, Journal of biomolecular screening.

[6]  W. Pitt,et al.  Identification of novel fragment compounds targeted against the pY pocket of v‐Src SH2 by computational and NMR screening and thermodynamic evaluation , 2007, Proteins.

[7]  Tudor I. Oprea,et al.  The Design of Leadlike Combinatorial Libraries. , 1999, Angewandte Chemie.

[8]  P. Leeson,et al.  The influence of drug-like concepts on decision-making in medicinal chemistry , 2007, Nature Reviews Drug Discovery.

[9]  Jocelyn Kaiser,et al.  Industrial-Style Screening Meets Academic Biology , 2008, Science.

[10]  C. Tisné,et al.  NMR-guided fragment-based approach for the design of tRNA(Lys3) ligands. , 2007, Angewandte Chemie.

[11]  Manfred Auer,et al.  Single‐bead, Single‐molecule, Single‐cell Fluorescence , 2008, Annals of the New York Academy of Sciences.

[12]  C. Murray,et al.  The rise of fragment-based drug discovery. , 2009, Nature chemistry.

[13]  A. Hopkins Network pharmacology: the next paradigm in drug discovery. , 2008, Nature chemical biology.

[14]  John P. Overington,et al.  How many drug targets are there? , 2006, Nature Reviews Drug Discovery.

[15]  Christopher L. McClendon,et al.  Reaching for high-hanging fruit in drug discovery at protein–protein interfaces , 2007, Nature.

[16]  W Frank An,et al.  Introduction: cell-based assays for high-throughput screening. , 2009, Methods in molecular biology.

[17]  John R. Proudfoot,et al.  Discovery and Development of Nevirapine , 2006 .

[18]  T. Blundell,et al.  Probing hot spots at protein-ligand binding sites: a fragment-based approach using biophysical methods. , 2006, Journal of medicinal chemistry.

[19]  Gordon M. Cragg Paclitaxel (Taxol®): A success story with valuable lessons for natural product drug discovery and development , 1998, Medicinal research reviews.

[20]  T Neumann,et al.  SPR-based fragment screening: advantages and applications. , 2007, Current topics in medicinal chemistry.

[21]  Laurent Ségalat,et al.  Invertebrate animal models of diseases as screening tools in drug discovery. , 2007, ACS chemical biology.

[22]  Oliver Dürr,et al.  Robust Hit Identification by Quality Assurance and Multivariate Data Analysis of a High-Content, Cell-Based Assay , 2007, Journal of biomolecular screening.

[23]  Huck-Hui Ng,et al.  Molecules that promote or enhance reprogramming of somatic cells to induced pluripotent stem cells. , 2009, Cell stem cell.

[24]  Thomas J. Crisman,et al.  Which aspects of HTS are empirically correlated with downstream success? , 2008, Current opinion in drug discovery & development.

[25]  C. Tralau-Stewart,et al.  Drug discovery: new models for industry-academic partnerships. , 2009, Drug discovery today.

[26]  David A. Price,et al.  Maraviroc (UK-427,857), a Potent, Orally Bioavailable, and Selective Small-Molecule Inhibitor of Chemokine Receptor CCR5 with Broad-Spectrum Anti-Human Immunodeficiency Virus Type 1 Activity , 2005, Antimicrobial Agents and Chemotherapy.

[27]  W Frank An,et al.  Cell-Based Assays for High-Throughput Screening , 2010, Molecular biotechnology.

[28]  John S Lazo,et al.  Building a Pharmacological Lexicon: Small Molecule Discovery in Academia , 2007, Molecular Pharmacology.

[29]  Xiao Xu,et al.  The application of cell‐based label‐free technology in drug discovery , 2008, Biotechnology journal.

[30]  Michael Williams,et al.  Drug Discovery and Development , 1987, Humana Press.

[31]  Daniel James,et al.  Lessons Learnt from Assembling Screening Libraries for Drug Discovery for Neglected Diseases , 2007, ChemMedChem.

[32]  J Richard Archer,et al.  History, evolution, and trends in compound management for high throughput screening. , 2004, Assay and drug development technologies.

[33]  N. Socci,et al.  High-throughput screening assay for the identification of compounds regulating self-renewal and differentiation in human embryonic stem cells. , 2008, Cell stem cell.

[34]  Li Di,et al.  Profiling drug-like properties in discovery research. , 2003, Current opinion in chemical biology.

[35]  E. Krausz,et al.  Cell-based high-content screening of small-molecule libraries. , 2007, Current opinion in chemical biology.

[36]  P. Hajduk,et al.  Discovery of a potent inhibitor of the antiapoptotic protein Bcl-xL from NMR and parallel synthesis. , 2006, Journal of medicinal chemistry.

[37]  Charles C Hong,et al.  Large-scale small-molecule screen using zebrafish embryos. , 2009, Methods in molecular biology.

[38]  Sam Michael,et al.  A robotic platform for quantitative high-throughput screening. , 2008, Assay and drug development technologies.