Precompetitive collaboration makes plans to enhance target validation and accelerate the discovery of new medicines
A public–private research initiative known as the Center for Therapeutic Target Validation (CTTV), which is led by GlaxoSmithKline (GSK; London, UK), the European Bioinformatics Institute (EMBL-EBI; Cambridge, UK) and the Wellcome Trust Sanger Institute (Hinxton, UK), plans to harness the power of genomics, big-data analysis, disease biology and translational medicine in a precompetitive collaboration aimed at improving success rates in early drug discovery.
The collaboration intends to draw on the expertise of the Wellcome Trust Sanger Institute in the role of genetics in health and disease, while EMBL-EBI will provide bioinformatics-led insights on the data and use its capabilities to integrate huge streams of different varieties of experimental data. GSK will contribute expertise in disease biology, translational medicine and drug discovery.
CTTV states that it will be supported by up to 50 researchers from the three founding organizations and will be based on the Wellcome Trust Genome Campus near Cambridge, UK. Researchers will use EMBL-EBI's Innovation and Translation suite, which received substantial support from the UK government in 2012, and the laboratories of the Wellcome Trust Sanger Institute. The CTTV has been established with significant contributions of resource, skills and platform technologies from each of the three founding organizations and a multimillion pound contribution by GSK to fund an initial wave of projects.
Under the terms of the collaboration, sequence data and information gathered within the CTTV will be shared to benefit the broader scientific community, after basic quality control checks to ensure consistency with the data-sharing guidelines of both institutes have been carried out. The center will also seek publication of data and information arising from CTTV projects in peer-reviewed scientific journals. Once the center is fully established, the collaborators will actively seek to attract new interest from other companies and academic institutions in the centre with the aim of expanding its activities.
Ewan Birney, Associate Director and Senior Scientist at EMBL-EBI, and Interim Head of the CTTV commented: “The precompetitive nature of the center is critical: the collaboration of EMBL-EBI and the Sanger Institute with GSK allows us to make the most of commercial R&D practice, but the data and information will be available to everyone. It is truly exciting to apply so many different areas of expertise, from data integration to genomics, to the challenge of creating better medicines.”
– Written by Hannah Coaker
Source: EMBL-EBI press release: www.ebi.ac.uk/about/news/press-releases/CTTV-launch
A group from the University of Geneva (Geneva, Switzerland) in collaboration with researchers at the Geneva-Lausanne School of Pharmacy (Geneva, Switzerland) has developed a new drug-discovery approach aimed at addressing the challenges of designing selective inhibitors.
Due to the high sequence conservation of druggable pockets of closely related proteins the development of selective inhibitors can be problematic. The team's novel approach moves towards circumventing this issue by exploiting both the static and dynamic differences of two orthologues.
As a proof-of-concept, the group, which is led by Didier Picard, professor at the Faculty of Sciences of the University of Geneva, applied the approach in the identification of compounds that discriminate between the molecular chaperone Hsp90 of the protozoan pathogen Plasmodium falciparum and that of its human host.
The team reports that the ATP-binding pocket has a P. falciparum-specific extension, whose sequence lining is identical in human Hsp90, but which differs by tertiary structure and dynamics. Using these insights to conduct a structure-based drug screen, the group discovered novel 7-azaindole compounds that exclusively bind the recombinant N-terminal domain of PfHsp90 but not that of human Hsp90 or a PfHsp90 mutant.
In terms of future work, the team now plans to optimize a group of patented molecules related to the 7-azaindoles, with a view to performing clinical tests.
– Written by Hannah Coaker
Source: Wang T, Bisson WH, Mäser P, Scapozza L, Picard D. Differences in conformational dynamics between Plasmodium falciparum and human Hsp90 orthologues enable the structure-based discovery of pathogen-selective inhibitors. J. Med. Chem. 57(6), 2524–2535 (2014).
Scientists based at Johns Hopkins University School of Medicine (MD, USA) have discovered that an experimental cancer drug, FRAX486, appears to reverse schizophrenia-associated behavior and restore some of the lost neuron communication in adolescent mice. FRAX486 is part of the PAK inhibitor class of compounds; this class of inhibitors has previously been tested against Alzheimer's disease and cancer.
This study, led by Akira Sawa (Professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine), found that FRAX486 halted the destructive ‘pruning’ process that destroys important neural connections, and could also partially restore the affected neurons, allowing them to connect again. Sawa commented, “By using this compound to block excess pruning in adolescent mice, we also normalized the behavior deficit. That we could intervene in adolescence and still make a difference in restoring brain function in these mice is intriguing.”
Using adolescent mice that mimic the progression of schizophrenia, the Johns Hopkins team turned down the expression of DISC1. The protein associated with this gene regulates neurons in the cerebral cortex, therefore a DISC1 shortage leads to destruction of spines (parts of the neurons that help them to communicate).
A shortage of DISC1 also affects KAL7 production, a protein that regulates Rac1 protein development. If there is a DISC1 deficit, KAL7 cannot control Rac1 production, and it is believed that this excess Rac1 erases spines leading to excess PAK. Therefore,it was observed on day 35 and 60, equivalent to adolescence and young adulthood, that if FRAX486 is used to inhibit PAK activity, this halts the destruction of spines caused by too little DISC1 and also restores missing spines. It was found that the PAK inhibitor-based drug was able to improve the behavior of the mice, through testing of their reactions to noises.
However, it has not yet been proven that PAK inhibitors are elevated in humans with schizophrenia, this must therefore be validated. Sawa concluded, “Drugs aimed at treating a disease should be able to reverse an already existing defect as well as block future damage. This compound has the potential to do both.”
– Written by Lisa Parks
Sources: Experimental cancer drug reverses schizophrenia in adolescent mice. www.hopkinsmedicine.org/news/media/releases/experimental_cancer_drug_reverses_schizophrenia_in_adolescent_mice; Hayashi-Takagi A, Araki Y, Nakamura M et al. PAKs inhibitors ameliorate schizophrenia-associated dendritic spine deterioration in vitro and in vivo during late adolescence. Proc. Natl Acad. Sci. USA doi:10.1073/pnas.1321109111 (Epub ahead of print) (2014).
A group from Massachusetts General Hospital (MA, USA) has described the structural basis for the design of safer ligand-mimicking integrin inhibitors, which have therapeutic potential in treating a number of conditions, ranging from heart attacks to cancer metastasis.
Integrins are receptor proteins found on the surface of cells that determine whether or not cells adhere to adjacent cells and the surrounding extracellular matrix. If integrins become overactive, cells become too 'sticky', leading to clogged arteries, pathological inflammation, fibrosis or cancer metastasis.
Current RGD-based anti-integrin drugs have been known to lead to a number of complications in the patient as they can also act as partial agonists. “Integrins have an intrinsic ability to shape-shift when they switch from an inactive to an active, adhesive state” explains M Amin Arnaout, who led the study. “Unfortunately, under some circumstances the integrin inhibitors that have been developed to date can inadvertently induce this shape shifting and, consequently, use of these drugs has produced serious, sometimes fatal side effects such as excessive bleeding.”
In an effort to design a new and safer generation of anti-integrin drugs, the group conducted a study into fibronectin, which is known to bind to integrin, αvβ3. By carrying out detailed structural analysis of the bond between αvβ3 and various forms of FN10, the fibronectin molecule that interacts with αvβ3, the team identified a high-affinity version of FN10 that binds more strongly than the common form without causing unintended receptor activation.
The group's findings could offer new insights into the mechanism of integrin activation and a basis for the design of a new generation of RGD-based pure antagonists, which are free of the complications that have so far limited their application.
– Written by Hannah Coaker
Source: Van Agthoven JF, Xiong J-P, Alonso JL et al. Structural basis for pure antagonism of integrin αVβ3 by a high-affinity form of fibronectin. Nat. Struct. Mol. Biol. doi:10.1038/nsmb.2797 (2014) (Epub ahead of print).
A team of scientists has reported that cathepsin B (CatB) gene knockout, or its reduction by an enzyme inhibitor, blocks the creation of key neurotoxic pGlu-Aβ peptides, which are linked to Alzheimer's disease (AD).
pGlu-Aβ peptides are N-terminally truncated forms of full-length Aβ peptides (flAβ(1-40/42)), in which the N-terminal glutamate is cyclized to pyroglutamate to generate pGlu-Aβ(3-40/42). β-secretase cleavage of amyloid-β precursor protein (AβPP) produces flAβ(1-40/42), but it was not yet known whether the β-secretase BACE1 or the alternative β-secretase CatB participate in the production of pGlu-Aβ.
To illuminate on the origin of pGlu-Aβ, Hook and colleagues examined the effects of gene knockout of these proteases on brain pGlu-Aβ levels in transgenic AβPPLon mice, which express AβPP isoform 695 and have the wild-type β-secretase activity that is found in most AD patients. The team discovered that knockout or overexpression of the CatB gene reduced or increased, respectively, pGlu-Aβ(3-40/42), flAβ(1-40/42) and pGlu-Aβ plaque load, but knockout of the BACE1 gene had no effect on those parameters in the transgenic mice. The group also found that E64d, an enzyme inhibitor of CatB, reduced production of pGlu-Aβ and other AD-associated Aβ peptides.
“This is an exciting finding, as it addresses a new target – CatB – and an effective, safe small molecule, E64d, to reduce the pGlu-Aβ that initiates development of the disease's neurotoxicity. No other work in the field has addressed protease inhibition for reducing pGlu-Aβ of AD.”
The safety of E64d has already been demonstrated in clinical trials of patients with muscular dystrophy and, as such, the group anticipates that the inhibitor will likely prove safe for treating AD. Hook hopes to launch Phase I human clinical trials in the near future with a modified version of the drug candidate.
– Written by Hannah Coaker
Source: Hook G, Yu J, Toneff T, Kindy M, Hook V. Brain pyroglutamate amyloid-beta is produced by cathepsin B and is reduced by the cysteine protease inhibitor E64d, representing a potential Alzheimer's disease therapeutic. J. Alzheimers Dis. doi:10.3233/JAD-131370 (2014) (Epub ahead of print).