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Cambridge MedChem Consulting

Target validation and antibodies

A couple of years ago I mentioned an article reviewing antibody selectivity

In 2011, an evaluation of 246 antibodies used in epigenetic studies found that one-quarter failed tests for specificity, meaning that they often bound to more than one target. Four antibodies were perfectly specific — but to the wrong target.

The issue of antibody selectivity has again been flagged as a concern in oestrogen receptor beta research DOI. This is a major target for breast cancer research and there are multiple ongoing clinical trials https://clinicaltrials.gov/ct2/results?term=ERβ.

We here perform a rigorous validation of 13 anti-ERβ antibodies, using well-characterized controls and a panel of validation methods. We conclude that only one antibody, the rarely used monoclonal PPZ0506, specifically targets ERβ in immunohistochemistry.

Applying this antibody for protein expression profiling in 44 normal and 21 malignant human tissues, we detect ERβ protein in testis, ovary, lymphoid cells, granulosa cell tumours, and a subset of malignant melanoma and thyroid cancers. We do not find evidence of expression in normal or cancerous human breast.

Perhaps more worryingly the authors comment.

While our study focuses on ERβ, we do not think that antibodies towards ERβ are significantly poorer than those targeting other proteins, and it is not unlikely that this problem generates similar obstacles in many other fields.

As I wrote on the Target Validation page

Remember this is an absolutely critical step, almost everything else can be fixed.

Computational Tools Updated

I've updated the computational tools page in the Drug Discovery Resources.

Encouraging early results for the drug delaying onset of Motor Neurone discovered by artificial intelligence

Motor neurone disease (MND) describes a group of diseases that affect the nerves (motor neurones) in the brain and spinal cord, is is likely that there are multiple molecular targets. Amyotrophic lateral sclerosis (ALS) also known as Lou Gehrig's disease is the most common form of MND. Edaravone was recently approved for the treatment of ALS but the mechanism is unknown. It is a free radical scavenger and oxidative stress has been hypothesised to be part of the process that kills neurones in people with ALS. However new treatments are urgently needed.

For this reason I was particularly interested to read about a potential novel treatment for ALS arising from work between Benevolnet.ai and Sheffield Institute for Translational Neuroscience.

The study, led by Dr. Richard Mead and Dr. Laura Ferraiuolo at SITraN, assessed the efficacy of a drug candidate proposed by BenevolentAI's artificial Intelligence technology for Motor Neuron Disease (MND), also known as Amyotrophic Lateral Sclerosis (ALS). SITraN found there are significant and reproducible indications that the drug prevents the death of motor neurones in patient cell models, and delayed the onset of the disease in the gold standard model of ALS…Dr. Richard Mead of SITraN commented: "This is an exciting development in our research for a treatment for ALS. BenevolentAI came to us with some newly identified compounds discovered by their technology - two of which were new to us in the field and, following this research, are now looking very promising. Our plan now is to conduct further detailed testing and continue to quickly progress towards a potential treatment for ALS."

SITraN expect to publish an abstract at the Motor Neurone Disease Association 28th International Symposium in Boston in December 2017.

Heart on a chip

Cardiotoxicity is a major hurdle for all drug discovery programs and so I'm always interested in ways that any potential liabilities can be flagged without the need to go into whole animals. A recent publication highlights progress in developing a novel model system.

Human induced pluripotent stem cell-derived cardiomyocytes were cultured as a model system, and used to validate the platform with an excitation–contraction decoupling chemical. Preliminary data using the platform to investigate the effect of the drug norepinephrine are combined with computational efforts. This platform provides a quantitative and predictive assay system that can potentially be used for comprehensive assessment of cardiac toxicity earlier in the drug discovery process. DOI.

ChEMBL_23 released

ChEMBL_23 has been released, it was prepared on 1st May 2017 and contains:

  • 2,101,843 compound records
  • 1,735,442 compounds (of which 1,727,112 have mol files)
  • 14,675,320 activities
  • 1,302,147 assays
  • 11,538 targets
  • 67,722 source documents

Data can be downloaded from the ChEMBL ftp site: ftp://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/releases/chembl_23
Also includes

Deposited Data Sets
CO-ADD, The Community for Open Antimicrobial Drug Discovery, is a global open-access screening initiative launched in February 2015 to uncover significant and rich chemical diversity held outside of corporate screening collections. CO-ADD provides unencumbered free antimicrobial screening for any interested academic researcher.  CO-ADD has been recognised as a novel approach in the fight against superbugs by the Wellcome Trust, who have provided funding through their Strategic Awards initiative. Open Source Malaria (OSM) is aimed at finding new medicines for malaria using open source drug discovery, where all data and ideas are freely shared, there are no barriers to participation, and no restriction by patents. The initial set of deposited data from the CO-ADD project consists of OSM compounds screened in CO-ADD assays (DOI = 10.6019/CHEMBL3832881).

Modelled on the Malaria Box, the MMV Pathogen Box contains 400 diverse, drug-like molecules active against neglected diseases of interest and is available free of charge (http://www.pathogenbox.org). The Pathogen Box compounds are supplied in 96-well plates, containing 10 uL of a 10mM dimethyl sulfoxide (DMSO) solution of each compound. Upon request, researchers around the world will receive a Pathogen Box of molecules to help catalyse neglected disease drug discovery. In return, researchers are asked to share any data generated in the public domain within 2 years, creating an open and collaborative forum for neglected diseases drug research. The initial set of assay data provided by MMV has now been included in ChEMBL (DOI = 10.6019/CHEMBL3832761).

The European Lead Factory Works!

The European Lead Factory (ELF) is a collaborative public-private partnership aiming to deliver novel lead molecules for drug discovery programs. When the consortium was formed around 5 years ago there was a lot of scepticism about whether a group of 30 partners rating from large Pharma companies to small academic groups could ever agree on a legal framework that would allow the ELF to function. In a addition, in an industry where confidentiality was critical to maintaining intellectual property the idea that a group of large Pharma companies would share their sample collections often regarded as the "Crown Jewels" seemed impossible. However I was at the European Lead factory Stakeholder Meeting (24-25 April 2017) and it is clear that is has been a success.

Read More…

FDA approves deutetrabenazine

The FDA have approved deutetrabenazine, the deuterated analog of tetrabenazine, for chorea associated with Huntington disease. This represents an example of perhaps the simplest bioisostere and the first example to gain FDA approval.

Deutetrabenazine

There are several other examples of the H to D change to reduce the rate of metabolism and improve pharmacokinetics.

First Disclosures at ACS San Francisco

The ACS session organised by Division of Medicinal Chemistry includes a day of first disclosures of potential clinical candidates for the first time. Beth Halford was there and tweeted a series of hands drawn structures as they were disclosed. I've redrawn the structures and converted them into a single sdf file. I've also used Jupyter Notebook to calculate the physicochemical properties and plot them as shown in the image below.

test2png

As can be seen, many of the compounds are on the large size with molecular weights >450, a third of them have ionisable groups which serves to bring down the calculated LogD. All molecules contain an aromatic ring, indeed many contain multiple rings. Interestingly we see a number of examples where a biphenyl ring system bears multiple ortho substituents presumably locking the two aryl rings orthogonal, no mention of atrope isomers though. This might also reduce the planarity and increase the 3D shape.

The sdf file is available here FirstDisclosures.sdf.zip if anyone spots any errors in the structures please let me know.

Drug Discovery Resources Updates

I've been updating the Drug Discovery Resources section.

In particular I've added a section on target prediction tools, updated the section on Analysis of HTS data, and expanded the section on aggregation in bioassays to include a recent publication giving an example of target specific aggregation.

The crystal structure showing the interaction is available (PDB 5MU8) and is displayed below using 3Dmol.js, the ligand (JNJ525) is shown in red..

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In addition I've updated the section on molecular interactions.

European Lead factory Newsletter

The latest issue of the European Lead Factory Newsletter has just been published.

Highlights include the European Lead Factory recently reached the milestone of having received over 1,000 chemical library proposals for consideration. To date, 143,529 novel compounds, out of the 200,000 prospected compounds for the Public Compound Collection, have been synthesized, which means that the ELF compound collection grows daily by approximately 250 novel compounds to eventually constitute the 500,000 Joint European Compound Library (JECL).

Parkinson’s UK and the University of Sheffield have launched a joint venture biotech company, Keapstone Therapeutics. Parkinson’s UK has allocated 1 million GBP over the next sixteen months to further develop compounds that boost the internal cellular defence mechanisms against oxidative stress. These compounds were discovered by European Lead Factory.