ELRIG (European Laboratory Robotics Interest Group) Drug Discovery 2012

Last week, a few of the Sssex Translational Drug Discovery Group were able to attend ELRIG (European Laboratory Robotics Interest Group) Drug Discovery 2012 held at Manchester GMEX conference center (and this year for once we even got some sunshine).

ELRIG has become the UK’s main Drug Discovery conference. The numbers of delegates attending was about 1200, ranging from big pharma, biotech’s, vendors and other drug discovery groups from academic sector. I found the lectures very interesting, focusing on areas such as biophysical screening, compound management, primary and stem cells, fragment screening and assay development.

If I had to give the conference an overall theme it probably would be, pharma companies encouraging collaborative work with academic groups and also the increasing return to phenotypic based screening. To me this seems to be “knock on” effect from the reduction in research from pharma, with many groups looking to supplement their business models and improve the success rate of finding new compounds that make it to market. I guess from these initiatives it is hoped improvements can be made in areas such as target identification and target validation. From the vendor side of conference it seemed many companies have now launched HCS reader platforms. Another field which seems to have moved on at a pace was 3D cell culture with a lot of different vendors launching these types of products to make  in vitro tissue culture  more representative of in vivo.

Some highlighted lectures for me included:

1.) Dr Edward Ainscow from Novartis discussed, a phenotypic based screen run against three different parasites species with a 650,000 compound file in collaboration with an academic partner, which produced a wide selection of hit material. These were then further triaged via cytotoxic detection assays for further study. This is a good example of pharma offering it facilities and compound files which most academic groups would not access too.

2.) Peter Simpson from Astra Zeneca, highlighted a similar programme which aims to give academic groups access to big screening files – the “IMI European screening factory”(hopefully launching next year).  The remit of this facility is to screen at least 48 screening assay projects (24 from public projects and 24 from pharma projects) in a year. A large number of the compounds in the screening file (about 500,000 compounds) will be donated from the Pharma industry.  The number of HTS run in a year does seem a quite a high target from my experience, given the problem of assay transfer between the small bench top to 1536 well plate HTS (not always seamless to say the least). There are still a lot of issues that remain unclear to me; intellectual property, assay development, reagent costs. but I’ll watch this space keenly as this has a lot of potential for academic groups.


Steve Rees from Astra Zeneca (and the outgoing chairman of ELRIG) gave the closing address, with a good summary of current UK drug discovery and what the future could bring. He highlighted the growth of academic groups such as the SGC (structural genomics consortium) and Dundee Drug Discovery unit which was positive. He did mention that the medical chemistry aspect of the drug discovery process seemed to be less well resourced and that needs addressed for success. I know the last few years have not been great for medical chemists in the UK, but I’m sure it’s nice to hear someone say you’re important!

Overall the ELRIG 2012 was very good meeting.  Everyone who organises this conference (most of them in their spare time) should be applauded for another success. I look forward to ELRIG 2013 in hopefully another sunny Manchester.

Gareth Williams



Will major IMI collaborations help understand drug-induced liver injury?

Drug-induced liver injury, or DILI, is a major concern for the development and sustained sale of drugs.  For the 548 NCEs that were approved in the US from the mid-seventies to the end of the century, adverse drug reactions led to 16 approved drugs being withdrawn and 56 being given black box warnings.  A recent article in Nature Reviews Drug Discovery highlights a major new project in the Innovative Medicines Initiative (IMI) which will provide €32 million to a consortium of 17 industry & 9 academic partners.  The article also points out a couple of well-worked examples which make the point of the current lack of understanding.  The first, panadiplon, a GABA-A partial agonist being developed for non-sedating anxiety was terminated in Phase I over a decade ago due to liver injury despite no evidence for related toxicity in rat, dog or monkey pre-clinical tox.  This was discussed in more depth by Abbott in a paper over 10 years ago, which discusses some additional toxicology in rabbits which was later discovered to have some connection with the human observations.  This paper nicely illustrates the need for both more openness on the part of sharing toxicology data and also the challenges of interpreting the data across species.

The second example plucked from the other end of the spectrum is CAL-101, a phosphoinositide-3 kinase δ inhibitor in development for various leukaemias.  This molecule also showed liver toxicity in Phase I despite no warnings pre-clinically, but this toxicity has been manageable and the agent has progressed to Phase III, leading to the acquisition of Calistoga by Gilead (and the renaming of the drug to GS-1101).  The review of the tox and clinical data is covered in a very interesting set of blog articles.

Many papers have appeared over the last few years dealing with the hopelessness of ever understanding these problems as well as some more pragmatic approaches – many are referenced from a recent blog or the 2010 NRDD paper on chemically reactive metabolites.  This new IMI project seeks to combine data sets from toxicology studies and to both evaluate existing models and devise new mechanistic platforms (with emphasis on human derived rather than animal in vivo) to improve future prediction of DILI.  The goals are clearly aspirational and the sharing of toxicology data more widely is absolutely essential, however these large EU projects provide a challenging framework to make rapid progress.

Antibacterial drug discovery is hard work

The area has rightly acquired a reputation as a graveyard for drug hunters. With many big pharma research groups exiting the area over the last 15 years those remaining are to be applauded because undoubtedly the need for new, effective antibacterials remain high.

This seems to be an area prone more than most to the ‘latest idea’. Ten years ago genomics was going to allow us to identify all the essential targets and then prosecute them in a logical manner. The widespread failure of this “pile ‘em high/screen ‘em quick” approach (including the high-profile demise of the GSK group) has pushed many of the remaining companies back in the opposite direction towards screening natural product collections or libraries of dross DOS compounds. So it’s encouraging to find groups who have had the courage to retain their heads whilst all around were losing theirs.  Whilst AZ senior management have not covered themselves with glory over the last few years, in this case their persistence is to be applauded.

What marks this publication ( http://pubs.acs.org/doi/abs/10.1021/cb300316n ) out is the successful progression of a novel anti-bacterial target from target identification, through to validating the target with lead molecules in an in vivo model. The authors suggest this is only the second time this has been done in the last 10 years.

Thymidylate kinase (TMK) is the enzyme that transfers phosphate from ATP to thymidine monophosphate to form thymidine diphosphate. It is essential for survival of cells because blockade stops DNA replication. TMK sits at the junction of the de novo and salvage metabolic pathways and has been explored as an antiviral and antimycobaterial target in the past. However, the difficulty of identifying good quality molecules has prevented TMK from being validated in vivo.

Unlike protein kinases, where the ATP molecule is buried in a lipophilic cleft, in TMK the ATP site is relatively solvent exposed meaning the most ‘druggable’ site is that which binds thymidine monophosphate. This also has the advantage of being the site that shows most difference when compared to the human orthologue and hence holds out the potential for achieving selectivity. Taking thymine as a starting point the authors made a series of heterocyclic analogues, attempting to mimic the sugar ring system with additional liphophilic substituents trying to pick up interactions with an identified hydrophobic pocket. TK-924 was their starting point for optimisation.

The authors describe an optimisation programme which made over 1000 compounds, each synthesised via a 10- to 15-step synthetic route-a truly Herculean effort! One wonders how many of the compounds were made at AZ and how many were made on contract (and perhaps sometimes the efforts of the CRO are never appropriately acknowledged!). Nevertheless optimisation led to TK-666. The synthesis is described in the supplementary material but for those of you who like to see such things here is the route-

The compound showed good enzyme activity against Gram positive bacteria, excellent selectivity vs. the human orthologue and good antibacterial activity (<1ug/ml) vs. pathogenic Gram-positive bacteria (including resistant strains). In the standard thigh model the compound showed efficacy at 100mg/kg by administration of a single intraperitoneal dose. Perhaps disappointingly the dosing route and activity point towards improvements that still need to be addressed by the medicinal chemistry programme.

Nevertheless an interesting new set of antibacterial compounds worthy of further exploration.

C-H activation showcase

C-H activation has been a hot subject for the last few years with many groups investing much effort in removing the need for organo-metallic derivatives that can prove a challenge of their own to generate. Despite many efforts in what sometimes looks more like ‘black art’ than planned selectivity, the direct arylation of pyrazoles has been one of the toughest challenges of the past 10 years. The likes of Daugulis and Sames have established methodologies involving Cu catalysis and SEM directing groups to enable the direct arylation onto pyrazoles.

 A recent publication from Doucet’s group at the Université de Rennes showcases the introduction of a sacrificial heteroatom to address the selectivity of aryl moieties onto pyrazoles by direct arylation.


The initial C-H activation is worth a few words here as the reaction is catalysed by a phosphine free palladium used in very low loading (0.1%). A considerable advantage over the typical conditions, especially as such processes find their way into pilot plants and commercial routes. No mention however as to why the reaction undergoes C-H activation with such a system. Also of interest, the authors claims the arylation proceeds via a Concerted Metalation Deprotonation (CMD) mechanism. Although there are no explanations, it is interesting to note that in this case pivalic acid, normally added to lower the energy of the C-H bond cleavage, is not used in this CMD reaction.

The reaction prefers para- and meta- electron withdrawing aryl bromide substituents with yields mostly ranging in the 70 to 80%.


Of most interest is the direct arylation of pyridyls, quinolones and isoquinolines, all obtained in high yield. A real ‘tour de force’ if you have ever tried to introduce a boron to either a pyridyl or a pyrazole without suffering subsequent protodeborylation during the cross coupling.

Dehalogenation in the presence of 5% Pd/C enables the further direct arylation at the C-5 position, this time using a palladium with a phosphine ligand.


Overall, a good example of how powerful the C-H activation methodology can be in coupling hetero aromatics moieties together

This article can only lead to a comparison to the excellent Sames’ article published in JACS (previously mentioned in my introduction and to which the author also refers to) a few years ago. Sames used nitrogen protected SEM group to direct the selectivity to the adjacent carbon.