Transcriptomics-based Phenotypic Screening Supports Drug Discovery in Human Glioblastoma Cells

IOTA releases a new paper on transcriptomics-based phenotypic screening by Shapovalov et al. and is getting ready for product commercialization:

Glioblastoma (GBM) remains a particularly challenging cancer, with an aggressive phenotype and few promising treatment options. Future therapy will rely heavily on diagnosing and targeting aggressive GBM cellular phenotypes, both before and after drug treatment, as part of personalized therapy programs. Here, we use a genome-wide drug-induced gene expression (DIGEX) approach to define the cellular drug response phenotypes associated with two clinical drug candidates, the phosphodiesterase 10A inhibitor Mardepodect and the multi-kinase inhibitor Regorafenib. We identify genes encoding specific drug targets, some of which we validate as effective antiproliferative agents and combination therapies in human GBM cell models, including HMGCoA reductase (HMGCR), salt-inducible kinase 1 (SIK1), bradykinin receptor subtype B2 (BDKRB2), and Janus kinase isoform 2 (JAK2). Individual, personalized treatments will be essential if we are to address and overcome the pharmacological plasticity that GBM exhibits, and DIGEX will play a central role in validating future drugs, diagnostics, and possibly vaccine candidates for this challenging cancer.


European Commission and selected IOTA Pharmaceuticals as one of the top 8 healthcare start-ups

Selection of start-ups was conducted together with EC's Innovation Radar and Horizon Result Platform. The competition is exceptionally interesting as all the companies have previously received significant non-dilutive EU grant funding. This funding has already allowed IOTA to develop sophisticated products and the following round of investment is needed for IOTA for market expansion and expansion of clinical network.


Transcriptomics predicts compound synergy in drug and natural product treated glioblastoma cells

Pathway analysis is an informative method for comparing and contrasting drug-induced gene expression in cellular systems. Here, we define the effects of the marine natural product fucoxanthin, separately and in combination with the prototypic phosphatidylinositol 3-kinase (PI3K) inhibitor LY-294002, on gene expression in a well-established human glioblastoma cell system, U87MG. Under conditions which inhibit cell proliferation, LY-294002 and fucoxanthin modulate many pathways in common, including the retinoblastoma, DNA damage, DNA replication and cell cycle pathways. In sharp contrast, we see profound differences in the expression of genes characteristic of pathways such as apoptosis and lipid metabolism, contributing to the development of a differentiated and distinctive drug-induced gene expression signature for each compound. Furthermore, in combination, fucoxanthin synergizes with LY-294002 in inhibiting the growth of U87MG cells, suggesting complementarity in their molecular modes of action and pointing to further treatment combinations. The synergy we observe between the dietary nutraceutical fucoxanthin and the synthetic chemical LY-294002 in producing growth arrest in glioblastoma, illustrates the potential of nutri-pharmaceutical combinations in targeting this challenging disease.


    We have created IOTA as a resource to support the emerging areas of fragment-based drug discovery, structure-based drug design, high-content drug screening and lead optimization, key areas of modern drug discovery.On this page we summarise our key publications and place them in the context of emerging science covering IOTA's core interests of cancer and infectious disease.

    Selected IOTA Publications

    • Fragment-based drug discovery of phosphodiesterase inhibitors

    Mini Perspective on the use of fragment based methods for the design of phosphodiesterase inhibitors, authored by IOTA scientists in collaboration with the University of Cambridge

    • Phenotypic screening in cancer drug discovery — past, present and future

    A paper by Genentech scientists Dr John Moffat and Dr Joachim Rudolph and the IOTA scientist Dr David Bailey, describing the emerging relationships between target-based drug discovery and phenotypic drug discovery in cancer research

    • Fragment-based screening in tandem with phenotypic screening provides novel antiparasitic hits

    VU and IOTA scientists Dr David Bailey and Dr Paul England describe the discovery of new antiparasitic compounds using fragment-based techniques

    • Surface plasmon resonance biosensor assay for the analysis of small-molecule inhibitor binding to human and parasitic phosphodiesterases

    A screening technology paper co-authored by IOTA's assay expert Dr Paul England

    Review publications covering IOTA's core programmes

    • Twenty years on: the impact of fragments on drug discovery

    A summary of the impact of fragment based drug discovery over the last twenty years

    • G-protein-coupled receptors and cancer

    A review of the role of G-protein receptors in cancer and their use as therapeutic targets

    • Primary brain tumours in adults

    Overview of the most common brain tumours, their epidemiology and current treatments

    • Drug discovery and development for neglected parasitic diseases

    Review on the development of drugs for neglected parasitic diseases