The ‘Pathogen Box’


Last year I (Ryan West) attended the ISNTD-D3 2015 conference where I saw a presentation by Julio Martin from GSK Tres Cantos. He gave an interesting talk about open source drug discovery focusing on kinetoplastid diseases. One of the highlights of the talk for me was the introduction of three 200 compound collections that have been phenotypically identified as inhibitors of trypanosoma brucei, trypanosoma cruzi or leshmania donovani.

The collections were generated by screening a 1.8 million compound library from GSK against the pathogens in question. Hits were filtered to remove cytotoxic compounds and undesired structural features. The compound collections have been made available to public and private partners to facilitate research into neglected tropical diseases. Efficacy and cytotoxicity data has been published on ChEMBL and highlighted in Nature Scientific Reports 5: 8771 doi:10.138/srep08771.

Recently there has been a move towards encouraging and facilitating research into neglected tropical diseases. Medicines Malaria Venture (MMV) released a box of 400 compounds in 2011 that were active against the blood stage form of the P. falciparum parasite. Again, these compounds were freely available to the research community for further scientific investigation. This resulted in more than 40 publications, the depositing of publicly accessible data from over 20 screens and the initiation of at least 3 medicinal chemistry programs for a range of neglected tropical diseases.

Continuing from the success of the ‘Malaria Box’ initiative MMV have been awarded a further grant from the Bill and Melinda Gates foundation to collate another library of compounds. This time the molecules have been identified phenotypically against a broader range of 8 unique pathogens which are responsible for a large proportion of the world’s neglected tropical diseases. The collection has been available from December 2015, and as part of my project I have been able to acquire one of the kits for testing. We are interested in an enzyme target responsible for the blood stream respiration of the parasite that causes human African trypanosomiasis. We hope to publish our results in the near future.

This open source approach of sharing compound collections along with generated experimental data will boost research and aid the discovery of novel molecules for treating neglected tropical diseases. It will be interesting to see the progress of these open source endeavours and if they will be more widely adopted by other disease areas.

 

Blog written by Ryan West

Multidrug Co-Crystals Leading to Improved and Effective Therapeutics in Drug Development


In the last ten years, research has been focused on alternative therapeutic strategies for drug development and one of them is co-crystals. A review of the development, production and future of co-crystals has recenlty been published by Thipparaboina R. and co-workers .

The definition of co-crystals given by the FDA is “solids that are crystalline materials composed of two or more molecules in the same crystal lattice”, usually the interactions between molecules are weak, having non-colavent interactions. The discovery of the first co-crystal structure was quinhydrone complex synthesise by Friedrich Wohler in 1844, he found that this co-crystal was composed of a 1:1 ratio of quinone and hydroquinone. In drug development a co-crystal or multidrug co-crystal (MDC) is an active pharmaceutical ingredient (API) with a neutral compound in the same crystal lattice with non-ionic interactions between the two.

The interest in co-crystals for the pharmaceutical industry has increased in the last ten years, thanks to the development of multidrug co-crystals, for example the recent success of the phase II clinical trial of Celecoxib and Tramadol drugs by ESTEVE and Muldipharma Laboratories GmbH for the treatment of acute pain. There is a large list of existing multidrug co-crystals, their interactions improve solubility and bioavailability in therapeutic treatments. Some examples are, Ethenzamide and Gentisic acid which increase the solubility and dissolution rate (Srinivasulu et al., 2009); Meloxicam and Aspirin that significantly increase bioavailability (Cheney et al., 2011).  Co-crystals give the opportunity to treat a specific group of patients with one drug. The multidrug co-crystal Sildenafil and Aspirin presented dual therapeutic effects, treating erectile dysfunctions in cardiovascular complication patients (Zegarac et al., 2014). The following table lists the multidrug co-crystals developed so far.

thalia

thalia2

The production of multidrug co-crystals is similar to normal crystallography procedures, however, the success depends on several factors and a deep understanding of both components to co-crystalize. Important factors to consider in the production of MDC are temperature, presence of impurities, rates of evaporation, differential solubility, solvent properties, supersaturation, cooling, etc. Scaling up the production of MDC is feasible and successful, several techniques such as spherical co-crystallization, spray-drying technologies, solvent crystallization, sonic crystallization and others have been used for the production of co-crystals (Fig1).

thalia3

 

In 2013 the Food and Drug Administration (FDA) released a regulatory guideline for the classification of pharmaceutical co-crystals and soon after, in 2014, the European Medicines Agency (EMA) released a paper on the use of co-crystals in pharmaceutical research, however there are no many regulatory guides for the pharmaceutical market. At the moment there are few marketed co-crystal products, such as Entresto (Sacubitril-Valsartan), approved by the FDA in 2015, for the treatment of heart failure, and Lexapro (Escitalopram Oxalate), approved in 2009, for the treatment of major depressive and anxiety disorders. For the pharmaceutical industry it could be quite challenging to patent MDC and their method of production. In addition, every patent office requires different criteria for co-crystals registration. Every year the number of patents granted to multidrug co-crystals by the European Patent Office (EPO) and the United States Patent Office (USPTO) has increased. The patents available currently in MDC are listed in table 2.

thalia4.png

It is a challenge for pharmaceutical research and industry to find appropriate drug co-crystals combinations for the therapeutic and pharmaceutical market. However, several factors need to be considered for the production of MDC, such as incompatibility between compounds, impurities, differential solubility and dose variability. The latter is an important factor to be considered for optimal success of MDC. For example, the common stoichiometry of co-crystals is a 1:1 ratio, however some dose range between drugs are variable and the slight increase of dose of one can modify or cause undesirable side effects to the patient. The development of validated predicted models for MDC is required to avoid pitfalls.

On the other hand, novel treatments for psychiatric disorders and neuropathic pain can be approached with the used of lithium and magnesium salts to form multidrug co-crystals. Also nanotechnology can be used for the production of nano-crystals for drug delivery or clinical applications.

The pharmaceutical industry needs be aware of the different considerations in terms of multidrug co-crystals such as, predicted models, FDA regulations, patents, safety and bioavailability. Although challenging multidrug co-crystals could be a novel approach for developing an effective therapeutic, however the commercial success hasn’t emerged rapidly. There needs to be further investment in research for the development of multidrug co-crystals.

Blog written by Thalia Carreno Velazquez

 

 

References

Cheney, M.L. et al. (2011) Coformer selection in pharmaceutical cocrystal development: a case study of a meloxicam aspirin cocrystal that exhibits enhanced solubility and pharmacokinetics. J. Pharm. Sci. 100, 2172–2181

Srinivasulu, A. et al. (2009) Trimorphs of a pharmaceutical cocrystal involving two active pharmaceutical ingredients: potential relevance to combination drugs. CrystEngComm 11, 1823–1827.

Thipparaboina, R. et al. (2016) Multidrug co-crystals: towards the development of effective therapeutic hybrids. Drug Discov Today 21, 481-490.

Zegarac, M. et al. (2014) A sildenafil cocrystal based on acetylsalicylic acid exhibits an enhanced intrinsic dissolution rate. CrystEngComm 16, 32–35

Chemical and Biological Therapeutic Approaches to Neurological Disorders Symposium


On Monday 18th April, the 3rd symposium on Chemical and Biological Therapeutic Approaches to Neurological Disorders took place at Burlington House in London. Dr Paul Beswick and I (Tristan Reuillon) represented the Sussex Drug Discovery Centre (SDDC) at this one day conference, organised by the Royal Society of Chemistry. Paul gave a talk on the use of structural biology for the design of ligands for glutamate ionotropic receptors, an approach which has been and is being used on different projects at the SDDC, while I presented a poster on recent developments in the field of AMPA receptor positive allosteric modulators.

Some of the leading researchers in the field of neuroscience were presenting, such as Dr Eric Karran, former head of research at Alzheimer Research UK now at AbbVie or Prof John Hardy from UCL, recent winner of the Breakthrough Prize in Life Sciences for his pioneering research into the genetic causes of Alzheimer’s disease (AD). Dementia was the major focus of the symposium, with Dr Eric Karran introducing the statistics on AD and giving a detailed overview of the different theories believed to underlie AD (amyloid-beta (Aβ) and tau pathologies). According to Dr Karran the readouts of some critical clinical trials on AD drugs within the next two years will be extremely important to understand if the drug discovery efforts have been heading in the right direction and to guide further the current research on dementia. Prof John Hardy presented the genetic causes behind AD and amyloid deposition, with an emphasis on some specific proteins, such as TREM2, which represent very attractive drug discovery targets. Prof Nigel Hooper from the University of Manchester presented research focussed on Aβ, trying to identify what forms of Aβ oligomers and fibrils are neurotoxic and trying to link the alpha-secretase ADAM10 with Aβ production. Finally Dr Suchira Bose from Eli Lilly gave an in-depth analysis of the tau pathophysiology and different modulations of this physiological pathway which could lead to novel therapeutic approaches to AD.

Other neurological disorders were also discussed during the symposium. Dr Hasane Ratni from Roche presented the discovery of RG7800, a drug currently tested in phase II clinical trials for the treatment of Spinal Muscular Atrophy, a rare neurodegenerative disease affecting mainly children. RG7800 acts as a SMN2 splicing modifier. Dr Richard Mead from the University of Sheffield talked about his current research on Motor Neuron Disease, also termed Amyotrophic Lateral Sclerosis, with a focus on the NRF2-ARE pathway, an indicator and modulator of oxidative stress in neurodegeneration. Different attempts to identify activators of this pathway, such as apomorphine, were discussed. The presentation of Dr Paul Beswick on glutamate potentiators was centred on the identification of novel drugs to treat the cognitive dysfunction associated with Schizophrenia, a major symptom, for which there is a clear unmet medical need. Finally, Prof Kristian Stromgaard from the University of Copenhagen, presented a few drug discovery approaches that his group has undertaken to disrupt protein-protein interactions in the CNS, such as the PSD-95-NMDA interaction. Owning to the lack of success in identifying small molecule hits, his research has focussed on peptidomimetics, which are surprisingly brain penetrant and are currently in preclinical development.

I found this symposium extremely interesting, with some fantastic and innovative research being disclosed, and would highly recommend it for anyone interested in neuroscience research. I hope to have given you through this blog article a flavour of the different topics which were discussed on that day and maybe tempted you to attend the 4th symposium in this series which will take place next year.

 

Blog written by Tristan Reuillon

The pharmaceutical industry: ‘doing the right things and doing the things right’?


The pharmaceutical industry is constantly under pressure to satisfy demands of the healthcare sector and to ensure business survival in terms of return on R&D investment. The main objective is to deliver drug candidates of the highest possible quality to decrease the risk of failure in clinical phases during the development process. The authors of this review have analysed the current key strategies emerging from the different R&D approaches to achieve this objective.

A notable change that has occurred in the pharmaceutical industry over the last few decades is the move from the drug discovery process that was exclusively conducted within pharmaceutical organizations to the current open innovation model, characterised by strong collaborations among pharmaceutical industries, academia and other industries with the development of a new and sustainable funding model with public and academic participations.

The focus of current R&D business relies on a costly, risky and time-consuming strategy to find first-in-class medicines, based on the discovery of new targets, with the aim to treat diseases with as-yet no treatment or to deliver more efficacious drugs in the pipeline than those currently on offer. This addiction to blockbuster drugs can be partly explained by the pharmaceutical industry needs to produce sustainable revenues and returns on investment for shareholders.

However, projects based on new targets have less probability to reach the market than those based on known targets, and the later entrants – where research is based on known targets – displace the first-in-class products in the market place, even if the first entrant has the exclusivity free of competition during a period of time. The focus on first-in-class products based on new targets alone is not enough to solve the current productivity gap. These days, pharmaceutical companies producing such first-in-class drug candidates often develop a ‘follow-on’ drug based on the more validated (with the first drug) target to reduce the risk of obtaining no drug approval. Getting the right balance between first-in-class products based on new targets and second-in-class products, as well between target-based and phenotypic approaches, constitutes a lifeline offering the chance to resolve the drug pipeline attrition.

Failures in clinical trials have soared over the past 20 years, with attrition rates between 1990 and 2010 increasing for Phase I from 33% to 46%, for Phase II from 43% to 66% and for Phase III from 20% to 30%. The main reasons for failure (Fig. 1) at Phase II are insufficient efficacy (51%), safety concerns (19%) and strategic issues (29%); and reasons for Phase III failures are predominantly insufficient efficacy (66%) and safety concerns (21%). The failures during early stages are less costly than those at Phase III; therefore implementing strategies to identify them as early on in the process as possible is absolutely crucial.

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Figure 1. Main reasons for clinical failures by Phase based on 410 drugs that entered human testing between 2000 and 2009. The main failures in Phase II and III studies are efficacy issues, 54% and 2%, respectively. Safety issues represent about one-third of all the 410 drugs analysed in Phase I and Phase III studies, versus 17% of all Phase II studies.

A new model is emerging in pharmacological research called polypharmacology, which describes the activity of compounds at multiple targets. The aim of multi-targeted approach is to avoid adverse side effects (safety parameters), and to improve therapeutic efficacy, prevent drug resistance or reduce therapeutic-target-related adverse side-effects (efficacy parameters). Generally, multitarget drugs – in combination or not – are more efficacious than single-target drugs, for instance in oncology and against viral infection. Furthermore, rather than a one-target therapy, polypharmacological modulation of a network of targets is actually required in the treatment of many multigenic diseases, as in the case of multikinase inhibitors that can block multiple targets in parallel signaling pathways and thereby prevent drug resistance caused by mutations or expression changes.

The failures due to pharmacokinetics/bioavailability issues currently account only to 1% for Phase II, reflecting the quality of the research process. The key points to consider in the drug discovery process are the right pharmacologic target and the right chemical lead. Reduction of timelines and cost (R&D) are strongly related to the high quality of science. The quality of the bioactive molecule can be evaluated using several criteria such as e-ADME profile including PK/PD behaviours, metrics, drug-like concept. The improvement of the quality of the target and bioactive molecule decrease the probability of failure in clinical trials.

The authors proposed (Fig. 2) a simple overview for new hit, lead and drug optimization process using the space concept strategy and several metrics to qualify these different chemical entities, based on the Lipinski and Hopkins concept of navigation and exploration of the chemical space.

The chemical space can be subdivided into four clusters associated with several specific chemical and physicochemical properties or topological descriptors as recognition patterns such as MW, clogP, number of hydrogen acceptors (NHA) and number of hydrogen donors (NHD) to define these discrete areas. Thus, druglike chemical space (Ro5, oral route, grey cube), lead-like chemical space (Ro4, green cube), fragment chemical space (Ro3, bright blue cube) and one mauve cube dedicated to the Ro50 for transdermal drugs can be represented. Other spaces dedicated to other administration routes can also be used (mauve cube). Inside the Ro5 (clinical candidates), Ro50 (clinical candidates) and Ro4 (leads), the use of the ligand efficiency (LE) as a simple indices or metric to quantify the molecular quality of the different chemical entity types, for selection and optimization inside each cluster. Other indices can be also used such as LLE, BEI/SEI, SIHE or QED. As shown, the optimization navigation process between each cluster can be performed using LE, LLE or BEI/SEI. Based on these metrics, construction of more ‘druggable’ libraries (from fragments, leads or drugs) can be developed. The overlapping of the drug-likeness chemical space continuum (Ro5, grey cube) and the 3D ‘target classes’ (block-cylinder, also called target space) including individually, for instance, PPI space, kinase space, G-protein-coupled receptor (GPCR) space, etc., defined an overlap volume (green rays, truncated cylinder) for which all the compounds (virtual or real) within this space are druggable; the anti-overlap area corresponds to the poorly druggable compounds. The same parameters used to define the boundaries of druggable compounds (e.g. Ro5) can be used to define a specific target space including drugs.

 

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Figure 2. Simple overview for new hit, lead and drug optimization process using the space concept strategy (real and virtual) and metrics to qualify chemical entities.

And to conclude, the authors stress the valid point made earlier by Elebring that ‘too much process thinking in drug discovery, such as Ro5, Ro3, etc., can block enthusiasm, creativity, intuition, innovation and serendipity’. Future success in drug discovery must therefore depend on achieving the correct balance between ‘doing the right things and doing the things right’.

 

Blog written by Irina Chuckowree

TMEM16/ANO: a pore of 2 halves


TMEM16 proteins are found in all eukaryotes, with the family consisting of ten genes (TMEM16A-K, missing out I).  Following TMEM16A and B being discovered as the elusive calcium activated chloride channels (CaCC) in 2008 by 3 independent groups (1, 2, 3) it was fully expected that all the other members of the family would also be CaCC’s because of their high sequence similarity.  However, this was not the case and TMEM16C-K have been shown to be phospholipid scramblases (4).  So how do TMEM16 proteins on the one hand scramble plasma membrane phospholipids, and on the other hand operate as anion channels?

In an attempt to answer this question Whitlock and Hartzell in their review (5) put forward a novel hypothesis: –

  • TMEM16A and B evolved from an ancestral scramblase.
  • TMEM16A pore shares structural similarity to an ancestral TMEM16 lipid channel.
  • The TMEM16A Cl selective pore is formed not of pure protein, as ion channel dogma is conceived at the moment, but is composed partly of lipids.

The authors propose that, TMEM16A protein stabilizes a non-bilayer phase in the membrane so that the 2 leaflets are continuous where they interact with the protein.  The lipid head groups would then provide a hydrophilic environment forming half of the pore and ions could move across the membrane in the ‘aqueous channel’ formed between the protein and the lipid head groups.  In putting forward this idea they have extrapolated Pomorki and Menon’s proposed mechanism for scramblases (6), in which a hydrophobic furrow would allow the phospholipid head groups to translocate from one side of the membrane to another while the acyl chains remain in the hydrophobic phase of the membrane, and suggest TMEM16A has evolved to conduct Cl ions but not lipids using the same conduction pathway.

They draw their evidence from the recent X-ray crystal structure of fungal nhTMEM16 provided by Brunner et al. (4) and then using their homology models show TMEM16A has a hydrophilic furrow very similar to that of nhTMEM16 with the exception of a patch of hydrophobic amino acids at the cytoplasm end of the furrow.  They suggest this patch might explain why TMEM16A is not a scramblase but an ion channel, because it forms a barrier to the movement of the hydrophilic head groups of phospholipids entering the furrow.

This is strengthened with reference to mutagenesis experiments where a chimeric protein was made with 35 amino acids from the lipid scrambling domain of TMEM16F and substituted into TMEM16A which them became a scramblase (7).  Suggesting this hypothesis might well be plausible, rather than as the title of Whitlock and Hartzell’s review suggests a poor idea, however, it needs further investigation to prove it right or wrong.

However, functional details remain obscure for most TMEM16 paralogs, making it unclear if they produce ion channels or not.  If this novel hypothesis is proven, it will have a major impact on our perception of the dogma of proteinaceous ion channels and the discovery of further TMEM16A inhibitors. It might also explain why TMEM16A inhibitors are, as the authors suggest, somewhat weird and not the ‘classical’ channel blockers, as it is unclear whether the current TMEM16 inhibitors block by acting in the permeation pathway or allosterically.

 

Blog written by Roy Fox

References:

 

 

 

Insight into the Pharmacokinetics of CNS Drugs: the Species-Independent Brain Tissue Binding Phenomenon


Neuroscience is one of the field of expertise of the Sussex Drug Discovery Centre, and as a medicinal chemist novice to this area of drug discovery, I decided to extend my knowledge of drug delivery to the brain and pharmacokinetics for central nervous system (CNS) pharmacological agents. A significant amount of extremely interesting literature covers neuropharmacokinetics, and I rapidly came across a number of essential principals such as the importance of high blood brain barrier (BBB) permeability or the complexity of predicting pharmacokinetics/pharmacodynamics (PK/PD) relationships for CNS drugs. Among these dozens of publications, one scientific article1 from a group of DMPK scientists at Pfizer particularly attracted my attention, since it was reporting that brain tissue binding is species-independent, something that I would not have expected to be true. Indeed, I was familiar with the well-known phenomenon of interspecies differences in plasma protein binding and would have expected the same for brain tissue binding. As a result, I got extremely curious in finding out why the story was different with brain tissues and how the team at Pfizer conducted their study to draw this conclusion.

Before getting into the details of this study, let’s first set the scene to refresh one’s knowledge of pharmacokinetics and make sure that we are all on the same page. One of the most important, well accepted and widely applied concept in drug discovery and development, used to establish PK/PD models among other things, is the free drug hypothesis. This concept stipulates that in vivo efficacy is solely determined by the free (unbound) drug concentration at the site of action rather than total (bound and unbound) drug concentration, and that only the free drug is able to distribute from the systemic circulation across membranes to tissues. This notion which is key to understand the action of all drugs becomes even more essential in the context of CNS pharmacological agents. Indeed, the CNS is an extravascular compartment separated from the systemic circulation by the BBB and only free drug from the plasma can cross this biological barrier. The capacity of a drug to diffuse through the BBB is referred to as CNS permeability or CNS penetration, and is controlled and influenced by a number of physicochemical properties. Once in the CNS, the drug undergoes binding to the brain tissues and only a portion of the free drug in the plasma is free in the CNS to exert a pharmacological effect.

A number of techniques have been developed and used to determine the unbound drug concentration in the brain, such as in vivo microdialysis, cerebrospinal fluid sampling, and a combined measurement of brain tissue binding and brain distribution from plasma and brain concentration time courses. The latest approach is routinely used in pharmaceutical research since it requires less compound-specific optimisation and provides a direct measurement in the compartment of interest. In addition, it is a less challenging, more reproducible and higher throughput technique than the other methods. The fraction unbound (fu) of drugs in brain tissues can be obtained from two different biological systems: brain homogenates or brain slices. Although brain slices are considered more physiologically relevant, brain homogenates are more widely used, since they are easier to handle and store than slices, and can be readily obtain from commercial suppliers. Both systems afford good correlation with each other, indicating that brain tissue binding is primarily governed by nonspecific binding to lipophilic components rather than binding to intact structural elements.

Similarly to plasma protein binding, brain tissue binding has been routinely determined in multiple species to account for any potential species dependence. However from 2007, a few studies using a limited number of drugs or a limited number of species indicated that brain tissue binding might be species-independent. Pfizer decided to conduct the present study to confirm the species-independent phenomenon of brain tissue binding and determine if it was not limited to certain species, certain classes of pharmaceutical agents or a certain nature of brain binding. With this objective, a large number of structurally diverse compounds, covering a wide range of physicochemical properties (logD from -1.43 to 6.01, MWt from 151 to 823 g/mol, tPSA from 12 to 220 Å2) and brain binding characteristics (fu from 0.0005 to 0.5) in multiple animal species, was selected. The brain tissue binding of these compounds was assessed in seven species and strains (Wistar Han rat, Sprague-Dawley rat, CD-1 mouse, Hartley guinea pig, beagle dog, cynomolgus monkey and human), commonly used in neuroscience drug discovery.

Rigorous statistical orthogonal regression was used to analyse the concordance of the data between species, strain and within strain. The results unambiguously demonstrate that the drugs unbound fractions were strongly correlated (R2 ranging from 0.93 to 0.99) across the various species and strains tested. Importantly, the cross-species/strain correlations were extremely similar to the interassay correlation with the same species. Statistical analysis were performed and indicated that no correction was required for the extrapolation of fraction unbound from one species to the other species/strains. These results suggest that determination of brain tissue binding in a single species can replace multispecies determinations. The authors argue that the difference in composition of the brain relative to the plasma is a likely cause of the species-independent nature of brain tissue binding. Indeed, the brain has a much higher lipid contents (11% lipid and 7.9% protein versus 0.65% lipid and 18% protein in the plasma) which could account for the predominant non-specific binding of drugs to brain tissues. The absence of species-specific brain proteins selectively binding to drugs could be another potential explanation.

As stated earlier, the results from this study allowed the DMPK scientists at Pfizer to conclude that measuring brain tissue binding is essential for drugs intended to be used as CNS pharmacological agents, but that a single species measurement is sufficient. In addition, these results demonstrated that brain tissue binding variations can be ruled out to explain observed interspecies differences in the behaviour of CNS drugs.

I personally found the scientific paper1 describing the above study extremely enlightening and hope that this blog article will be of interest to other medicinal chemists or scientists working in the field of neuroscience.

Blog written by Tristan Reuillon

 

References:

  1. Drug Metabolism and Disposition 2011, 39, 1270-1277, Species Independence in Brain Tissue Binding Using Brain Homogenates (doi: 10.1124/dmd.111.038778)

 

A one-pot copper-catalysed synthesis of all possible stereoisomers of 1,3-amino alcohols from enals and enones


This recent letter produced by the Buchwald group [1] at MIT describes a copper catalysed synthesis of amino alcohols by sequential hydrosilyalation and hydroamination of enals and enones ( Figure 1).yusuffig1

Figure 1. Synthesis of amino alcohols. [1]

The chirality of a drug can have a significant biological impact in drug discovery. The chirality is the ‘handedness’ of a molecule and the various isomers of a chiral compound, known as enantiomers, will exhibit a different 3-dimensional orientation in space and could therefore possess different biological activities as they are different ‘keys’ that could fit into different ‘locks’. The most infamous example of this phenomenon is the sedative thalidomide which resulted 10,000 cases in the 1950s of malformed infants with a 50% survival rate. It was found that (R)-thalidomide possessed sedative effects while (S)-thalidomide was severely teratogenic. Figure 2, taken from the Wikipedia page on thalidomide, clearly shows the differing space occupied by the two enantiomers of thalidomide.yusuffig2

Figure 2. Enantiomers of thalidomide represented as 2D drawings and 3D ball and chain structures

With drug discovery clearly in need of methods to obtain all possible enantiomers of a chiral compound in a relatively easy manner, asymmetric synthesis has come to the rescue over the past few decades with major advancements in enantioselective synthesis. However, what has been lacking are methods that give a unified route to all possible stereoisomers of a given product containing multiple contiguous stereocentres.

The asymmetric hydrosilylation/hydroamination of enals and enones produces optically pure 1,3-amino alcohols which could be required for a target compound or be used as a building block in asymmetric synthesis. The synthesis is a one-pot procedure where the pre-stirred catalytic mixture composed of the copper hydride based catalyst, ligand and silane reagent is added to the enone or enal for 15 minutes followed by addition of the hydroxylamine ester (amine source) which is stirred at 55 °C for 36 h.

The authors show that hydrosilylation occurs regioselectively at the carbonyl over the alkene functionality and that hydroamination also occurs in a regio- and stereoselective manner to ultimately allow all possible amino-alcohols with a high chemo-, regio-, diastereo and enantioselectivity. Catalytic control was achieved by starting from the appropriate choice of enal/enone (E or Z) and ligand enantiomer (R or S).

The method seems to be applicable to a variety of enals/enones and amino –bearing groups with yields above 60 % generally obtained. Yields were generally higher for enals over enones. In all cases diasterometric ratios were >95% and e.e (enantiomeric excess) >99 %. Most notably, it was shown that all 8 possible stereoisomers of the final compound could be achieved in high selectivity from appropriate starting enals and starting enones (Figure 3).

 

yusuffig3

Figure 3. All possible stereoisomers from the reaction of the enone 4 with dibenzylamine aminating reagent [1] (see Figure 1)

This method to synthesise all possible stereoisomers of 1,3-amino alcohols using readily available starting materials in a reliable and easy manner is a good example of asymmetric synthesis methods coming through in the literature in more recent times that allows assembling all possibilities in compounds with multiple sterocentres. I look forward to see further expansion in this particular area of asymmetric synthesis.

Blog writted by Yusuf Ali

References

[1] Shi SL, Wong ZL, Buchwald SL. Nature. 2016 Mar 28. doi: 10.1038/nature17191 [Epub ahead of print]

 

 

The Importance of Good Communication in Drug Development


A commentary published in Cell last month discusses how the quality of communication between and within institutions influences how successfully promising biological findings are translated into novel drug therapies.1

In the commentary it is suggested that most drug development programs which are ultimately successful proceed via a standard approach (Figure 1). In this figure the authors describe the steps involved in a typical drug development program and highlight key communication challenges associated with each.

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Figure 1. Communication Challenges Associated with the Process of Drug Development1

The first major challenge identified is regarding candidate therapeutic targets and lead compounds being “oversold” or published with insufficient technical review such that there is a high attrition rate when results cannot be replicated or confirmed by other researchers. A study is given as an example in which Amgen scientists attempt to confirm results from dozens of cancer research publications and only succeed in replicating the findings in six of 53 cases.2 Similar stories are all too familiar, and while the causes are still being widely discussed, the communication failure is very evident.

Attempts to address this issue have begun with changes to the manuscript review process. Some journals are employing a checklist for authors, intended to document the rigor with which experiments are conducted, e.g. Nature: Reporting Checklist For Life Sciences Articles, and other editors have expressed interest in having statisticians consult on certain manuscripts. As the authors point the finger particularly at academic research, they suggest that industry-based scientists with technical expertise be engaged, both in reviewing drug discovery reports and in consulting throughout projects. Although they acknowledge that nowadays experts with relevant knowledge are often embedded within academic institutions. In addition they suggest that editors should insist that reports include an honest communication of any limitations of novel targets or inhibitors but emphasise that this should not preclude publication.

The second challenge is associated with how drug discovery projects are executed. Typically the teams responsible for driving projects are comprised of an array of scientists from biology, medicinal chemistry, biochemistry, structural biology, etc. Although they share a common goal because each scientist is an expert trained in their specific discipline they often speak in different “languages”. The authors highlight that teams are required to make many pivotal decisions and suggest that these can only be well informed where experts avoid use of jargon such that all team members can understand and examine the vital information. They also propose that it is as important to communicate experimental failure as it is success. Appropriate scrutiny early in the day should translate into an improved success rate. Given as an example is an analysis of AstraZeneca’s drug development pipeline, which revealed that 40% of the projects classified as efficacy failures in Phase II were associated with a failure to link the molecular target to the intended disease indication.3

Thirdly the authors highlight a challenge regarding selecting the correct patient population as drugs enter clinical development. The PARP inhibitor, olaparib, is used as an example. Despite olaparib originally being shown to confer synthetic lethality in cancers with BRCA1 and BRCA2 mutations,4 initial clinical development utilised a larger, heterogeneous population and the inhibitor failed to demonstrate good efficacy, regrettably delaying the approval of the drug. Improved communication could have prevented this. To address the issue, the National Centre for Advancing Translational Science  has been established within the National Institutes of Health (NIH) to “transform the translational process so that new treatments and cures for disease can be delivered to patients faster”. It is suggested that educating future researchers and physicians in interdisciplinary science to improve communication will prove key to the success of precision medicine.

Finally the authors note that the biomedical community must better communicate with the public in attempt to explain the disappointing success rate of expensive drug development programs.

While disease biology is poorly understood it is inevitable that clinical experimentation will remain unpredictable. However, this commentary convincingly suggests that improved communication throughout the drug discovery process will improve efficiency and increase the likelihood of success.

Blog written by Katie Duffell

References

  1. Settleman, J. & Cohen, R. L. Communication in Drug Development : ‘“ Translating ”’ Scientific Discovery. Cell 164, 1101–1104 (2016). doi:10.1016/j.cell.2016.02.050
  2. Begley, C. G. & Ellis, L. M. Drug development: Raise standards for preclinical cancer research. Nature 483, 531–533 (2012). doi:10.1038/483531a
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