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P17-28 Drug discovery at the speed of sound

Multiple benchmark reports suggest that development costs of drugs are skyrocketing while the introduction of novel drugs is decreasing or at best, stagnating. This creates huge problems to the public sector of the health insurance and clearly, fundamental changes have to occur in the future. Part of the cost and time problem in pharma companies can be attributed to the preclinical drug discovery and development process involving expensive high throughput screening (HTS) and hit-to-lead campaigns using mostly traditional technologies. The non-regulatory phase of preclinical drug discovery and development is based on lengthy processes as target validation and selection, assay development, library screening, hit identification and validation, hit to lead (H-2-L) optimisation and PKPD studies. This phase takes typically between 2-5 years and involves hundreds of scientists.
Therefore, here we want to introduce a fundamentally novel approach towards preclinical drug discovery and development by blending Instant Chemistry, nL dispensing, acoustic-MS, uHTS and artificial intelligence. This technology platform is designated “Drug discovery at the speed of sound™”. This platform will allow speeding-up a considerable part of the early drug discovery and reducing the time for hit identification to a lead compound from 2-5 years to less than a month with personnel of less than 10 scientists.

The customer benefits are substantiated in considerable saving of both time and personnel during the early drug discovery process, which translates into much earlier drug entry to the market. For example, it is known that a blockbuster drug generates > $ 1 billion revenues per year. Thus, for every and each day that it is not on the market corresponds to a loss of > $ 2.7 million.

The technology platform consists of 5 pillars: Instant Chemistry, nL dispensing, acoustic-MS, uHTS and artificial intelligence.
1. Instant Chemistry (also called MCR chemistry) is a general technique to assemble drug-like compounds in just one synthetic step. It has been estimated that between 5 and 10% of the FDA approved compounds can be synthesized using MCR technology. The PI Dömling is a worldwide leading expert in this technology area and possesses a database of >600 MCR scaffolds accessible by this chemistry in a one-pot fashion. The chemical space of MCR is very large and comprises >1012 compounds based on available building blocks. This technology is best compatible with the second pillar, acoustic nL dispensing.
2. Acoustic droplet ejection (ADE) technology allows for the fast, contactless and accurate transfer of very small droplets (nL) from plate to plate of different high density formats. ADE has had a dramatic impact in different technology areas, including drug discovery, cancer research and genomic research and is used in many laboratories worldwide. However, ADE has never been used in miniaturization and acceleration of library synthesis for uHT to dramatically accelerate the preclinical drug discovery cycle. Based on the known speed of ADE, it is estimated the synthesis of >10.000 per day. Labcyte Inc, the world leader and part of the current consortium, will contribute to the ADE technology (http://www.labcyte.com/).
3. QC will be performed by acoustic mass spectrometry (AMS). The compound synthesis will be performed on high density plates (1536, up to 9000 well plates) and the reactions will not be purified. Therefore, quality control (QC) of the reactions is very important. Waters Inc. together with AstraZeneca, both collaborating companies in the consortium are currently working on the optimisation of a prototype of AMS (https://www.astrazeneca.com/what-science-can-do/Acoustic-mass-spec.html).
4. The synthesized and quality controlled compounds of steps 1-3 will be screened by uHTS techniques which are compatible in speed with the synthesis and QC steps. In principle, all screening methods should be adaptable to the platform, however due to speed restrictions we currently foresee protein affinity MS (Waters Inc., delivering samples to the mass spec at a rate of 3 per second) and SPR (off rate) as feasible methods to measure the compounds protein binding activity. An x-ray crystallography module is envisaged which will be realized at the DESY synchrotron beamline in Hamburg. The Helmholtz institute operating the beamline will be essential part of the consortium (http://www.desy.de/index_eng.html).
5. Artificial intelligence will be used to rank the compounds affinities towards the protein target and based on the results to design the next synthesis generation of compounds for the H-2-L process. This will lead to a never-seen-before fast cycle time for hit-2-lead progression in parallel on multiple scaffolds. Genetic algorithms (GA) have been used in the past in one of the PIs biotech companies to completely foster a very large chemical space of billions of compounds by the GA driven synthesis of less than 400 compounds in just 20 generations to reach potent low nM lead compounds (onlinelibrary.wiley.com/doi/10.1002/anie.199522801/full).

A participating group of large pharma and biotech companies will ensure that the technology platform development will be close to the market.
The technology platform will be implemented under the leadership of Prof Dömling (RUG), expert in Instant Chemistry and early drug discovery and serial entrepreneur. Collaborators from other Dutch knowledge institutes include Prof. Christian Ottmann (TU Eindhoven) with expertise in structure based drug design and protein crystallography and Prof. Hub Ovaa (University Leiden) with expertise in chemical biology. The project will be highly supported by multiple international pharma companies, biotech (Telesis Pharma BV) and instrument companies (Labcyte Inc., Waters Inc.) with special expertise in specific parts of the platform.

Initiatiefnemer(s) 
Prof. Alexander Domling (RUG); Dr. Matthew Groves (RUG); Dr. Georgios Gkouridis (ZIAM, RUG); Dr. Shabnam Shaabani (RUG); Dr. Konstantinos Neochoritis (Telesis Pharma BV); Prof. Christian Ottmann (TU Eindhoven); Prof. Hub Ovaa (University Leiden).
Topsector 1 
HTSM (inclusief ICT, Nanotechnologie en Medische Technologie)
Topsector 2 (indien van toepassing) 
Life Sciences en Health (exclusief Medische Technologie)
Topsector 3 (indien van toepassing) 
Chemie
Openbare bijeenkomst (optioneel) 
3 november 2017 - 11:00am
Contactpersoon 
Prof Alexander Domling
University of Groningen Department of Drug Design GRIP Antonius Deusinglaan 1 Postbus 196 9700 AD Groningen The Netherlands t: +3150-3633307 c: +491603706633