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Innovative approaches to the design and synthesis of small molecule libraries
Accepted Manuscript Preface Innovative approaches to the design and synthesis of small molecule libraries Adam Nelson, Didier Roche PII: DOI: Reference:
S0968-0896(15)00150-9 http://dx.doi.org/10.1016/j.bmc.2015.02.046 BMC 12109
To appear in:
Bioorganic & Medicinal Chemistry
Please cite this article as: Nelson, A., Roche, D., Innovative approaches to the design and synthesis of small molecule libraries, Bioorganic & Medicinal Chemistry (2015), doi: http://dx.doi.org/10.1016/j.bmc.2015.02.046
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Preface Innovative Approaches to the Design and Synthesis of Small Molecule Libraries Adam Nelson1 and Didier Roche2 1
Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds,
LS2 9JT, UK 2
115 Avenue Lacassagne, Lyon, F-69003, France
Molecular therapeutics continue to dominate Man’s ability to treat disease. However, the cost of developing new drugs has recently been estimated at ∼€2B.1
The generation of high
quality, innovative small molecule leads2 remains a major challenge in drug discovery particularly for emerging targets such as protein-protein interactions. Against this background of increasing costs, the rate of drug discovery has remained roughly constant for over 60 years.3
Improving research and development productivity has been framed as the grand
challenge for the pharmaceutical sector.1
To address the huge challenges associated with
discovering and developing new drugs, novel ways of working are needed. The European Lead Factory was launched in 2013 as an open innovation platform to facilitate the discovery of high quality, innovative leads for drug discovery.4,5 The €196M consortium is funded under the European Innovative Medicines (IMI) initiative, and involves 30 partners including seven pharmaceutical companies, small and medium-sized enterprises (SMEs) and universities. The initiative offers remarkable opportunities to facilitate the discovery of new small molecule leads – both to consortium members, and to other European universities and small biotechnology companies A key asset of the European Lead Factory is its compound collection – the Joint European Compound Library, JECL6 – which will be exploited in 240 high-throughput screens. Half of these screens will be undertaken by the pharmaceutical companies within the consortium, whilst the other half will be proposed by European academics and SMEs and performed in the consortium’s European Screening Centre. At the outset of the project, around 300,000 high quality compounds were contributed by the pharmaceutical companies within the consortium. However, a key project goal is to complement these compounds with an additional 200,000 compounds that are designed to explore new chemical spaces that is not typically addressed in traditional screening collections.
This newly designed collection is based on proposals for
libraries of (typically ∼1000) compounds that are submitted by academic or industrial chemists – from either within or outwith the consortium – using a web-based tool.5
Submitted
proposals are assessed by a committee with broad and complementary expertise against six specific criteria – molecular properties, synthetic tractability, novelty, diversity potential, structural features and innovative library design. The feasibility of selected proposals is then determined experimentally by consortium partners, before production of compounds that are ultimately added to the JECL.
Overall, an efficient pipeline leading to the addition of
distinctive screening compounds to the JECL has been established.7
1
This symposium-in-print8 focuses on innovative approaches to the design and synthesis of small molecular libraries. The issue features articles contributed by many partners within the European Lead Factory consortium, together with other leading practioners in the design and synthesis of innovative scaffolds and libraries. Together, these scientists have developed key approaches that can facilitate bioactive molecule discovery including diversity-oriented synthesis,
biology-oriented
synthesis.
The research described in this symposium-in-print illustrates many innovative
synthesis,
multicomponent
chemistry
and
activity-directed
chemical approaches that are amenable to library production to yield diverse and distinctive compounds that complement existing large compound collections.9 1.
S. M. Paul, D. S. Mytelka, C. T. Dunwiddie, C. C. Persinger, B. H. Munos, S. R. Lindborg and A. L. Schacht, Nat. Rev. Drug Discov. 2010, 9, 203-214.
2.
B. Munos, Nat. Rev. Drug Discov. 2009, 8, 959-968.
3.
P. Simpson and M. Reichman, Nat. Rev. Drug Discov. 2014, 13, 3-4.
4.
A. Mullard, Nat. Rev. Drug Discov. 2013, 12, 173-175.
5.
www.europeanleadfactory.eu, accessed: 8th January 2015.
6.
J. Besnard, P. S. Jones, A. L. Hopkins and A. D. Pannifer, Drug Discov. Today 2015,
7.
By the end of 2014, 468 library proposals had been submitted; 318 had been accepted
doi:10.1016/j.drudis.2014.08.014 for synthetic validation; 98 had been successfully validated experimentally; and around 40 000 screening compounds had been produced for addition to the JECL. 8.
We thank Verónica Estévez, Esther Vicente-García (VU Amsterdam) and Ruth Wong (TI Pharma) for designing the cover of this symposium-in-print.
9.
H. Wild, D. Heimbach and C. Huwe, Angew. Chem. Int. Ed. 2011, 50, 7452.
2
S0968-0896(15)00150-9 http://dx.doi.org/10.1016/j.bmc.2015.02.046 BMC 12109
To appear in:
Bioorganic & Medicinal Chemistry
Please cite this article as: Nelson, A., Roche, D., Innovative approaches to the design and synthesis of small molecule libraries, Bioorganic & Medicinal Chemistry (2015), doi: http://dx.doi.org/10.1016/j.bmc.2015.02.046
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Preface Innovative Approaches to the Design and Synthesis of Small Molecule Libraries Adam Nelson1 and Didier Roche2 1
Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds,
LS2 9JT, UK 2
115 Avenue Lacassagne, Lyon, F-69003, France
Molecular therapeutics continue to dominate Man’s ability to treat disease. However, the cost of developing new drugs has recently been estimated at ∼€2B.1
The generation of high
quality, innovative small molecule leads2 remains a major challenge in drug discovery particularly for emerging targets such as protein-protein interactions. Against this background of increasing costs, the rate of drug discovery has remained roughly constant for over 60 years.3
Improving research and development productivity has been framed as the grand
challenge for the pharmaceutical sector.1
To address the huge challenges associated with
discovering and developing new drugs, novel ways of working are needed. The European Lead Factory was launched in 2013 as an open innovation platform to facilitate the discovery of high quality, innovative leads for drug discovery.4,5 The €196M consortium is funded under the European Innovative Medicines (IMI) initiative, and involves 30 partners including seven pharmaceutical companies, small and medium-sized enterprises (SMEs) and universities. The initiative offers remarkable opportunities to facilitate the discovery of new small molecule leads – both to consortium members, and to other European universities and small biotechnology companies A key asset of the European Lead Factory is its compound collection – the Joint European Compound Library, JECL6 – which will be exploited in 240 high-throughput screens. Half of these screens will be undertaken by the pharmaceutical companies within the consortium, whilst the other half will be proposed by European academics and SMEs and performed in the consortium’s European Screening Centre. At the outset of the project, around 300,000 high quality compounds were contributed by the pharmaceutical companies within the consortium. However, a key project goal is to complement these compounds with an additional 200,000 compounds that are designed to explore new chemical spaces that is not typically addressed in traditional screening collections.
This newly designed collection is based on proposals for
libraries of (typically ∼1000) compounds that are submitted by academic or industrial chemists – from either within or outwith the consortium – using a web-based tool.5
Submitted
proposals are assessed by a committee with broad and complementary expertise against six specific criteria – molecular properties, synthetic tractability, novelty, diversity potential, structural features and innovative library design. The feasibility of selected proposals is then determined experimentally by consortium partners, before production of compounds that are ultimately added to the JECL.
Overall, an efficient pipeline leading to the addition of
distinctive screening compounds to the JECL has been established.7
1
This symposium-in-print8 focuses on innovative approaches to the design and synthesis of small molecular libraries. The issue features articles contributed by many partners within the European Lead Factory consortium, together with other leading practioners in the design and synthesis of innovative scaffolds and libraries. Together, these scientists have developed key approaches that can facilitate bioactive molecule discovery including diversity-oriented synthesis,
biology-oriented
synthesis.
The research described in this symposium-in-print illustrates many innovative
synthesis,
multicomponent
chemistry
and
activity-directed
chemical approaches that are amenable to library production to yield diverse and distinctive compounds that complement existing large compound collections.9 1.
S. M. Paul, D. S. Mytelka, C. T. Dunwiddie, C. C. Persinger, B. H. Munos, S. R. Lindborg and A. L. Schacht, Nat. Rev. Drug Discov. 2010, 9, 203-214.
2.
B. Munos, Nat. Rev. Drug Discov. 2009, 8, 959-968.
3.
P. Simpson and M. Reichman, Nat. Rev. Drug Discov. 2014, 13, 3-4.
4.
A. Mullard, Nat. Rev. Drug Discov. 2013, 12, 173-175.
5.
www.europeanleadfactory.eu, accessed: 8th January 2015.
6.
J. Besnard, P. S. Jones, A. L. Hopkins and A. D. Pannifer, Drug Discov. Today 2015,
7.
By the end of 2014, 468 library proposals had been submitted; 318 had been accepted
doi:10.1016/j.drudis.2014.08.014 for synthetic validation; 98 had been successfully validated experimentally; and around 40 000 screening compounds had been produced for addition to the JECL. 8.
We thank Verónica Estévez, Esther Vicente-García (VU Amsterdam) and Ruth Wong (TI Pharma) for designing the cover of this symposium-in-print.
9.
H. Wild, D. Heimbach and C. Huwe, Angew. Chem. Int. Ed. 2011, 50, 7452.
2