Ex Scientia: Commercialising Multi-Target Drug Design

Lead Research Organisation: University of Dundee
Department Name: College of Life Sciences

Abstract

The clinical efficacy and safety of a drug is determined by its activity profile across multiple proteins in the proteome. Therefore methods to rationally design drugs a priori against polypharmacology profiles of multiple proteins would have immense value in drug discovery. We have developed and experimentally validated a new approach for the discovery of ligands, by automatically designing compounds by evolution. The design method has been tested with the synthesis of 40 novel compounds and the assaying of 800 ligand-target predictions, of which 75% were confirmed correct. We propose to commercialise the algorithm into an innovative drug discovery platform. In particular we propose to scale the algorithm onto a cloud computing infrastructure to identify a portfolio of multi-target drug design opportunities. In addition we propose to extend the validation data of the algorithm from GPCR to kinase polypharmacology predictions.

Publications

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Besnard J (2012) Automated design of ligands to polypharmacological profiles. in Nature

 
Description The project demonstrated and experimental validated that automated design methods based on machine learning from big data and evolutionary optimisation can successful be applied to the algorithmic design of compounds with desired "multi-target" or polypharmacology profiles. The group's work has been published in Nature. We actively collaborate with experimentalists, such as Prof Bryan Roth (UNC), to test our predictions.

Automated design of ligands to polypharmacological profiles. Jérémy Besnard, Gian Filippo Ruda, Vincent Setola, Keren Abecassis, Ramona M. Rodriguiz, Xi-Ping Huang, Suzanne Norval, Maria F. Sassano, Antony I. Shin, Lauren A. Webster, Frederick R.C. Simeons, Laste Stojanovski, Annik Prat, Nabil G. Seidah, Daniel B. Constam, G. Richard Bickerton, Kevin D. Read, William C. Wetsel, Ian H. Gilbert, Bryan L. Roth and Andrew L. Hopkins, Nature, (2012) 492, 215-220 doi:10.1038/nature11691 (Full Article)
Exploitation Route Since completion of the grant a private company ex scientia Ltd has show the method can be applied to the design of 'bispecific' small molecules with dual action against two proteins.

http://www.exscientia.co.uk/bispecifics

The method has also been used by at least 4 pharmaceutical companies.

The company has grown year on year. The success of the company was recently recognised by the team winning the BBSRC Commercial Innovator of the Year Award in 2015.
Sectors Pharmaceuticals and Medical Biotechnology
URL http://www.exscientia.co.uk
 
Description The outputs of this grant are: 1) Automated design of ligands to polypharmacological profiles. Jérémy Besnard, Gian Filippo Ruda, Vincent Setola, Keren Abecassis, Ramona M. Rodriguiz, Xi-Ping Huang, Suzanne Norval, Maria F. Sassano, Antony I. Shin, Lauren A. Webster, Frederick R.C. Simeons, Laste Stojanovski, Annik Prat, Nabil G. Seidah, Daniel B. Constam, G. Richard Bickerton, Kevin D. Read, William C. Wetsel, Ian H. Gilbert, Bryan L. Roth and Andrew L. Hopkins, Nature, (2012) 492, 215-220 doi:10.1038/nature11691 (Full Article) 2) This project directly lead to the formation of Ex Scientia Ltd. a research-based, spin-out company from the University of Dundee focused on designing polypharmacology drugs using proprietary automated drug design technology. The company has signed research deals worth $6.3 million (excluding milestones and licensing payments) with three US Pharma companies and one Japanese pharma company, since September 2012, with no dilution of equity. www.exscientia.co.uk On behalf of the company Prof Hopkins was awarded the BBSRC Commercial Innovator of the Year Award in 2015.
First Year Of Impact 2012
Sector Pharmaceuticals and Medical Biotechnology
Impact Types Economic
 
Description Commercial alliance between Sunovion Inc and Ex Scientia Ltd 
Organisation Sunovion Pharmaceuticals, Inc.
Country United States 
Sector Private 
PI Contribution The grant lead to the foundation of Ex Scientia Ltd. Since 2012 Ex Scientia Ltd has signed four commercial collaborations of which one as been made public. Ex Scientia Ltd is applying the automated design methodology to the new challenge of designing against phenotypic data.
Collaborator Contribution Ex Scientia provide algorithmic and data modelling expertise and Sunovion provide drug discovery activities.
Impact The outcomes of this collaboration are confidential.
Start Year 2012
 
Description Exscientia-Evotec Immuno-oncology Joint Venture 
Organisation Evotec
Country Germany 
Sector Private 
PI Contribution Evotec AG (Frankfurt Stock Exchange: EVT, TecDAX, ISIN: DE0005664809) and ex scientia Ltd (Dundee, UK) today announced a collaboration with the objective to discover and develop first-in-class bispecific small molecule immuno-oncology therapies. Ex scientia will contribute its unique algorithmic design platform while Evotec, mainly through its Toulouse site, will be responsible for medicinal chemistry, in vitro and in vivo pharmacology as well as development capabilities and expertise. Application of bispecific small molecules is an exciting strategy to significantly expand and enhance efficacy beyond conventional single target therapies. The initial focus will be cancer-related adenosine targets which are increasingly recognised to play important roles in immuno-oncology. Combining adenosine-based mechanisms with related targets holds great promise in boosting efficacy and addressing larger patient populations through a single small molecule drug.
Collaborator Contribution Experimental resources: Chemical synthesis, assays, DMPK
Impact No public outputs yet.
Start Year 2016
 
Description Exscientia-Sanofi collaboration 
Organisation Sanofi
Country Global 
Sector Private 
PI Contribution Ex Scientia Ltd (Exscientia) is pleased to announce that it has agreed a strategic research collaboration, and license option agreement with Sanofi in the high-interest area of metabolic disease. Delivery of new therapies for metabolic disease (such as diabetes) is hampered by a paucity of single targets that are amenable to drug discovery. To address this challenge, Exscientia will apply its unique platform to identify and validate combinations of drug targets* that could work synergistically and be amenable to Exscientia's powerful bispecific-small-molecule design strategy - where a small molecule is designed to be compatible with two distinct drug targets. Starting with over a thousand disease-relevant target combinations, Exscientia will triage opportunities and prioritise those with promising bispecific binding potential. Target pairs fulfilling these initial tractability criteria will pass through to Exscientia's lead-finding platform in order to generate bispecific-small-molecule compounds that can further validate the biological hypothesis. Bispecific small molecules passing all these quality gates may progress to full candidate delivery projects for Sanofi. Rapid delivery of multiple bispecific opportunities will be empowered by a pipeline of Exscientia capabilities driven by Artificial Intelligence and enabled automated design. As part of this agreement, Exscientia will be responsible for all compound design, whilst chemistry synthesis will be delivered by Sanofi. Further assays, preclinical experiments and subsequent trials for compounds progressing to the clinic will be managed by Sanofi, where Sanofi exercises the license option. The commercial terms for this agreement include the payment of research funding in order to identify those target pairs with the best combination of chemical compatibility and strong biological relevance plus further funding for prioritised candidate delivery opportunities. For compounds reaching agreed delivery criteria, a series of milestones covering both non-clinical and clinical may be payable by Sanofi. Finally, any licensed products reaching the market will qualify for recurrent sales milestones.
Collaborator Contribution Chemistry synthesis will be delivered by Sanofi. Further assays, preclinical experiments and subsequent trials for compounds progressing to the clinic will be managed by Sanofi.
Impact No outputs made public to date.
Start Year 2016