Repurposing Metformin as Therapy for Prostate Cancer within the STAMPEDE Trial Platform.

Eur Urol. 2016 Dec;70(6):906-908

Authors: Gillessen S, Gilson C, James N, Adler A, Sydes MR, Clarke N, STAMPEDE Trial Management Group

Abstract
Metformin is a safe, well-tolerated, inexpensive treatment that can be given in addition to current standard-of-care therapies for prostate cancer. Its use might mitigate the deleterious side effects of castration and exert an additional anticancer effect. It will be incorporated in the STAMPEDE trial platform in summer 2016. This will test its true utility as a repurposed treatment for men with high-risk locally advanced or metastatic prostate cancer at first presentation.

PMID: 27450106 [PubMed - indexed for MEDLINE]

Repurposed drug screen identifies cardiac glycosides as inhibitors of TGF-β-induced cancer-associated fibroblast differentiation.

Oncotarget. 2016 May 31;7(22):32200-9

Authors: Coleman DT, Gray AL, Stephens CA, Scott ML, Cardelli JA

Abstract
The tumor microenvironment, primarily composed of myofibroblasts, directly influences the progression of solid tumors. Through secretion of growth factors, extracellular matrix deposition, and contractile mechanotransduction, myofibroblasts, or cancer-associated fibroblasts (CAFs), support angiogenesis and cancer cell invasion and metastasis. The differentiation of fibroblasts to CAFs is primarily induced by TGF-β from cancer cells. To discover agents capable of blocking CAF differentiation, we developed a high content immunofluorescence-based assay to screen repurposed chemical libraries utilizing fibronectin expression as an initial CAF marker. Screening of the Prestwick chemical library and NIH Clinical Collection repurposed drug library, totaling over 1700 compounds, identified cardiac glycosides as particularly potent CAF blocking agents. Cardiac glycosides are traditionally used to regulate intracellular calcium by inhibiting the Na+/K+ ATPase to control cardiac contractility. Herein, we report that multiple cardiac glycoside compounds, including digoxin, are able to inhibit TGF-β-induced fibronectin expression at low nanomolar concentrations without undesirable cell toxicity. We found this inhibition to hold true for multiple fibroblast cell lines. Using real-time qPCR, we determined that digoxin prevented induction of multiple CAF markers. Furthermore, we report that digoxin is able to prevent TGF-β-induced fibroblast contraction of extracellular matrix, a major phenotypic consequence of CAF differentiation. Assessing the mechanism of inhibition, we found digoxin reduced SMAD promoter activity downstream of TGF-β, and we provide data that the effect is through inhibition of its known target, the Na+/K+ ATPase. These findings support a critical role for calcium signaling during CAF differentiation and highlight a novel, repurposable modality for cancer therapy.

PMID: 27058757 [PubMed - indexed for MEDLINE]

Drug Target Commons: A Community Effort to Build a Consensus Knowledge Base for Drug-Target Interactions.

Cell Chem Biol. 2017 Dec 15;:

Authors: Tang J, Tanoli ZU, Ravikumar B, Alam Z, Rebane A, Vähä-Koskela M, Peddinti G, van Adrichem AJ, Wakkinen J, Jaiswal A, Karjalainen E, Gautam P, He L, Parri E, Khan S, Gupta A, Ali M, Yetukuri L, Gustavsson AL, Seashore-Ludlow B, Hersey A, Leach AR, Overington JP, Repasky G, Wennerberg K, Aittokallio T

Abstract
Knowledge of the full target space of bioactive substances, approved and investigational drugs as well as chemical probes, provides important insights into therapeutic potential and possible adverse effects. The existing compound-target bioactivity data resources are often incomparable due to non-standardized and heterogeneous assay types and variability in endpoint measurements. To extract higher value from the existing and future compound target-profiling data, we implemented an open-data web platform, named Drug Target Commons (DTC), which features tools for crowd-sourced compound-target bioactivity data annotation, standardization, curation, and intra-resource integration. We demonstrate the unique value of DTC with several examples related to both drug discovery and drug repurposing applications and invite researchers to join this community effort to increase the reuse and extension of compound bioactivity data.

PMID: 29276046 [PubMed - as supplied by publisher]

Development of inhalable hyaluronan/mannitol composite dry powders for flucytosine repositioning in local therapy of lung infections.

J Control Release. 2016 Sep 28;238:80-91

Authors: Costabile G, d'Angelo I, d'Emmanuele di Villa Bianca R, Mitidieri E, Pompili B, Del Porto P, Leoni L, Visca P, Miro A, Quaglia F, Imperi F, Sorrentino R, Ungaro F

Abstract
Flucytosine (5-fluorocytosine, 5-FC) is a fluorinated analogue of cytosine currently approved for the systemic treatment of fungal infections, which has recently demonstrated a very promising antivirulence activity against the bacterial pathogen Pseudomonas aeruginosa. In this work, we propose novel inhalable hyaluronic acid (HA)/mannitol composite dry powders for repositioning 5-FC in the local treatment of lung infections, including those affecting cystic fibrosis (CF) patients. Different dry powders were produced in one-step by spray-drying. Powder composition and process conditions were selected after in depth formulation studies aimed at selecting the 5-FC/HA/mannitol formulation with convenient aerosolization properties and drug release profile in simulated lung fluids. The optimized 5-FC/HA/mannitol powder for inhalation (HyaMan_FC#3) was effectively delivered from different breath-activated dry powder inhalers (DPI) already available to CF patients. Nevertheless, the aerodynamic assessment of fine particles suggested that the developed formulation well fit with a low-resistance DPI. HyaMan_FC#3 inhibited the growth of the fungus Candida albicans and the production of the virulence factor pyoverdine by P. aeruginosa at 5-FC concentrations that did not affect the viability of both wild type (16HBE14o-) and CF (CFBE41o-) human bronchial epithelial cells. Finally, pharmacokinetics of HyaMan_FC#3 inhalation powder and 5-FC solution after intratracheal administration in rats were compared. In vivo results clearly demonstrated that, when formulated as dry powder, 5-FC levels in both bronchoalveolar lavage fluid and lung tissue were significantly higher and sustained over time as compared to those obtained with the 5-FC solution. Of note, when the same 5-FC amount was administered intravenously, no significant drug amount was found in the lung at each time point from the injection. To realize a 5-FC lung concentration similar to that obtained by using HyaMan_FC#3, a 6-fold higher dose of 5-FC should be administered intravenously. Taken together, our data demonstrate the feasibility to deliver 5-FC by the pulmonary route likely avoiding/reducing the well-known side effects associated to the high systemic 5-FC doses currently used in humans. Furthermore, our results highlight that an appropriate formulation design can improve the persistence of the drug at lungs, where microorganisms causing severe infections are located.

PMID: 27449745 [PubMed - indexed for MEDLINE]

Repurposing the clinically approved calcium antagonist manidipine dihydrochloride as a new early inhibitor of human cytomegalovirus targeting the Immediate-Early 2 (IE2) protein.

Antiviral Res. 2017 Dec 21;:

Authors: Mercorelli B, Luganini A, Celegato M, Palù G, Gribaudo G, Loregian A

Abstract
Currently, there are no therapeutic alternatives to DNA polymerase inhibitors to treat human cytomegalovirus (HCMV) infections, a major threat for immunocompromised patients and pregnant women. Here, we explored the potential to repurpose manidipine dihydrochloride (MND), a calcium antagonist clinically approved to treat hypertension, as a new anti-HCMV agent. MND emerged in a previous drug repurposing screen to find early inhibitors of HCMV replication, and now we confirm that it inhibits in the low micromolar range the replication of different HCMV strains, including clinical isolates and viruses resistant to approved DNA polymerase inhibitors. The antiviral activity of MND is specific for HCMV over different both DNA and RNA viruses. Further experiments in HCMV-infected cells testing the effects of MND on viral DNA synthesis and viral proteins expression revealed that it halts the progression of the virus cycle prior to viral DNA replication and E genes expression, but after IE proteins expression. According to these results, we observed that the overall antiviral activity of MND involves a specific interference with the transactivating functions of the viral Immediate-Early 2 (IE-2) protein, an essential viral transcription factor required for the progression of HCMV replication. Given that the inhibitory concentration against HCMV is in the range of clinically relevant concentrations of MND in humans, and the mechanism of action differs from that of the other available therapeutics, this already approved drug is an attractive candidate for repurposing in alternative anti-HCMV therapeutic protocols.

PMID: 29274844 [PubMed - as supplied by publisher]

Disulfiram with or without metformin inhibits oesophageal squamous cell carcinoma in vivo.

Cancer Lett. 2017 Dec 20;:

Authors: Jivan R, Peres J, Damelin LH, Wadee R, Veale RB, Prince S, Mavri-Damelin D

Abstract
Oesophageal squamous cell carcinoma (OSCC) is highly prevalent in developing countries but there has been little recent progress into efficacious yet affordable treatment strategies. Drug repurposing is one attractive approach for cancer therapy. Disulfiram (DSF), used to treat alcoholism, inhibits cancer growth and we previously found that DSF perturbs protein degradation/turnover pathways in vitro. This was enhanced by combining DSF with the anti-diabetic drug metformin (Met). Here, we investigated DSF with/without Met, against OSCC in vivo. Nude mice injected subcutaneously with the human OSCC cell line WHCO1, were treated with 30 mg/kg or 50 mg/kg DSF three times per week, with/without Met for three weeks. DSF and DSF/Met-treated animals had significantly smaller tumours compared to untreated, vehicle and positive control cisplatin-treated groups. This effect for DSF was independent of copper, with no significant accumulation of copper in tumours, together with maintained proteasome activity. However, increases in total ubiquitinated proteins, LC3B-II, LAMP1 and p62 in DSF and DSF/Met groups, indicate that autophagy is inhibited. These findings show that DSF and DSF/Met significantly impede OSCC tumour growth in vivo and offer prospective alternative chemotherapy approaches for OSCC.

PMID: 29274360 [PubMed - as supplied by publisher]

Enhancing the Promise of Drug Repositioning through Genetics.

Front Pharmacol. 2017;8:896

Authors: Pritchard JE, O'Mara TA, Glubb DM

Abstract
The development of new drugs has become challenging as the necessary investments in time and money have increased while drug approval rates have decreased. A potential solution to this problem is drug repositioning which aims to use existing drugs to treat conditions for which they were not originally intended. One approach that may enhance the likelihood of success is to reposition drugs against a target that has a genetic basis. The multitude of genome-wide association studies (GWASs) conducted in recent years represents a large potential pool of novel targets for drug repositioning. Although trait-associated variants identified from GWAS still need to be causally linked to a target gene, recently developed functional genomic techniques, databases, and workflows are helping to remove this bottleneck. The pre-clinical validation of repositioning against these targets also needs to be carefully performed to ensure that findings are not confounded by off-target effects or limitations of the techniques used. Nevertheless, the approaches described in this review have the potential to provide a faster, cheaper and more certain route to clinical approval.

PMID: 29270124 [PubMed]

Structure based drug discovery for designing leads for the non-toxic metabolic targets in multi drug resistant Mycobacterium tuberculosis.

J Transl Med. 2017 Dec 21;15(1):261

Authors: Kaur D, Mathew S, Nair CGS, Begum A, Jainanarayan AK, Sharma M, Brahmachari SK

Abstract
BACKGROUND: The problem of drug resistance and bacterial persistence in tuberculosis is a cause of global alarm. Although, the UN's Sustainable Development Goals for 2030 has targeted a Tb free world, the treatment gap exists and only a few new drug candidates are in the pipeline. In spite of large information from medicinal chemistry to 'omics' data, there has been a little effort from pharmaceutical companies to generate pipelines for the development of novel drug candidates against the multi drug resistant Mycobacterium tuberculosis.
METHODS: In the present study, we describe an integrated methodology; utilizing systems level information to optimize ligand selection to lower the failure rates at the pre-clinical and clinical levels. In the present study, metabolic targets (Rv2763c, Rv3247c, Rv1094, Rv3607c, Rv3048c, Rv2965c, Rv2361c, Rv0865, Rv0321, Rv0098, Rv0390, Rv3588c, Rv2244, Rv2465c and Rv2607) in M. tuberculosis, identified using our previous Systems Biology and data-intensive genome level analysis, have been used to design potential lead molecules, which are likely to be non-toxic. Various in silico drug discovery tools have been utilized to generate small molecular leads for each of the 15 targets with available crystal structures.
RESULTS: The present study resulted in identification of 20 novel lead molecules including 4 FDA approved drugs (droxidropa, tetroxoprim, domperidone and nemonapride) which can be further taken for drug repurposing. This comprehensive integrated methodology, with both experimental and in silico approaches, has the potential to not only tackle the MDR form of Mtb but also the most important persister population of the bacterium, with a potential to reduce the failures in the Tb drug discovery.
CONCLUSION: We propose an integrated approach of systems and structural biology for identifying targets that address the high attrition rate issue in lead identification and drug development We expect that this system level analysis will be applicable for identification of drug candidates to other pathogenic organisms as well.

PMID: 29268770 [PubMed - in process]

A Review of Computational Drug Repositioning Approaches.

Comb Chem High Throughput Screen. 2017 Dec 20;:

Authors: Huang G, Li J

Abstract
Computational drug repositioning emerges as a new idea of drug discovery and development. Contrary to conventional routines, computational drug repositioning encompasses low risk and high safety. Some successful cases demonstrated its advantage. Therefore, a large number of computational drug repositioning approaches have been developed over the past decades. We summarized briefly these methods and classified them into target-based, gene-expression-based, phenome-based and multi-omics-based categories according to strategies of drug repositioning. We reviewed some representatives of computational drug repositioning methods in each category, with emphasis on detail of techniques and finally discussed developing trends of computational drug repositioning.

PMID: 29268682 [PubMed - as supplied by publisher]

Discovery of Surface Target Proteins Linking Drugs, Molecular Markers, Gene Regulation, Protein Networks, and Disease by Using a Web-Based Platform Targets-search.

Methods Mol Biol. 2018;1722:331-344

Authors: Yan B, Wang P, Wang J, Boheler KR

Abstract
Integration and analysis of high content omics data have been critical to the investigation of molecule interactions (e.g., DNA-protein, protein-protein, chemical-protein) in biological systems. Human proteomic strategies that provide enriched information on cell surface proteins can be utilized for repurposing of drug targets and discovery of disease biomarkers. Although several published resources have proved useful to the analysis of these interactions, our newly developed web-based platform Targets-search has the capability of integrating multiple types of omics data to unravel their association with diverse molecule interactions and disease. Here, we describe how to use Targets-search, for the integrated and systemic exploitation of surface proteins to identify potential drug targets, which can further be used to analyze gene regulation, protein networks, and possible biomarkers for diseases and cancers. To illustrate this process, we have taken data from Ewing's sarcoma to identify surface proteins differentially expressed in Ewing's sarcoma cells. These surface proteins were then analyzed to determine which ones were known drug targets. The information suggested putative targets for drug repurposing and subsequent analyses illustrated their regulation by the transcription factor EWSR1.

PMID: 29264813 [PubMed - in process]

Therapeutic drug repositioning using personalized proteomics of liquid biopsies.

JCI Insight. 2017 Dec 21;2(24):

Authors: Velez G, Bassuk AG, Colgan D, Tsang SH, Mahajan VB

Abstract
BACKGROUND: In patients with limited response to conventional therapeutics, repositioning of already approved drugs can bring new, more effective options. Current drug repositioning methods, however, frequently rely on retrospective computational analyses and genetic testing - time consuming methods that delay application of repositioned drugs. Here, we show how proteomic analysis of liquid biopsies successfully guided treatment of neovascular inflammatory vitreoretinopathy (NIV), an inherited autoinflammatory disease with otherwise poor clinical outcomes.
METHODS: Vitreous biopsies from NIV patients were profiled by an antibody array for expression of 200 cytokine-signaling proteins. Non-NIV controls were compared with NIV samples from various stages of disease progression. Patterns were identified by 1-way ANOVA, hierarchical clustering, and pathway analysis. Subjects treated with repositioned therapies were followed longitudinally.
RESULTS: Proteomic profiles revealed molecular pathways in NIV pathologies and implicated superior and inferior targets for therapy. Anti-VEGF injections resolved vitreous hemorrhages without the need for vitrectomy surgery. Methotrexate injections reversed inflammatory cell reactions without the side effects of corticosteroids. Anti-IL-6 therapy prevented recurrent fibrosis and retinal detachment where all prior antiinflammatory interventions had failed. The cytokine array also showed that TNF-α levels were normal and that corticosteroid-sensitive pathways were absent in fibrotic NIV, helping explain prior failure of these conventional therapeutic approaches.
CONCLUSIONS: Personalized proteomics can uncover highly personalized therapies for autoinflammatory disease that can be timed with specific pathologic activities. This precision medicine strategy can also help prevent delivery of ineffective drugs. Importantly, proteomic profiling of liquid biopsies offers an endpoint analysis that can directly guide treatment using available drugs.

PMID: 29263305 [PubMed - as supplied by publisher]

Evaluation of a systems biology approach to identify pharmacological correctors of the mutant CFTR chloride channel.

J Cyst Fibros. 2016 Jul;15(4):425-35

Authors: Pesce E, Gorrieri G, Sirci F, Napolitano F, Carrella D, Caci E, Tomati V, Zegarra-Moran O, di Bernardo D, Galietta LJ

Abstract
BACKGROUND: Mistrafficking of CFTR protein caused by F508del, the most frequent mutation in cystic fibrosis (CF), can be corrected by cell incubation at low temperature, an effect that may be mediated by altered expression of proteostasis genes.
METHODS: To identify small molecules mimicking low temperature, we compared gene expression profiles of cells kept at 27°C with those previously generated from more than 1300 compounds. The resulting candidates were tested with a functional assay on a bronchial epithelial cell line.
RESULTS: We found that anti-inflammatory glucocorticoids, such as mometasone, budesonide, and fluticasone, increased mutant CFTR function. However, this activity was not confirmed in primary bronchial epithelial cells. Actually, glucocorticoids enhanced Na(+) absorption, an effect that could further impair mucociliary clearance in CF airways.
CONCLUSIONS: Our results suggest that rescue of F508del-CFTR by low temperature cannot be easily mimicked by small molecules and that compounds with closer transcriptional and functional effects need to be found.

PMID: 26971626 [PubMed - indexed for MEDLINE]

Screening of chemical compound libraries identified new anti-Toxoplasma gondii agents.

Parasitol Res. 2017 Dec 19;:

Authors: Adeyemi OS, Sugi T, Han Y, Kato K

Abstract
Toxoplasma gondii is the etiological agent of toxoplasmosis, a common parasitic disease that affects nearly one-third of the human population. The primary infection can be asymptomatic in healthy individuals but may prove fatal in immunocompromised individuals. Available treatment options for toxoplasmosis patients are limited, underscoring the urgent need to identify and develop new therapies. Non-biased screening of libraries of chemical compounds including the repurposing of well-characterized compounds is emerging as viable approach to achieving this goal. In the present investigation, we screened libraries of natural product and FDA-approved compounds to identify those that inhibited T. gondii growth. We identified 32 new compounds that potently inhibit T. gondii growth. Our findings are new and promising, and further strengthen the prospects of drug repurposing as well as the screening of a wide range of chemical compounds as a viable source of alternative anti-parasitic therapeutic agents.

PMID: 29260298 [PubMed - as supplied by publisher]

Screening of a composite library of clinically used drugs and well-characterized pharmacological compounds for cystathionine β-synthase inhibition identifies benserazide as a drug potentially suitable for repurposing for the experimental therapy of colon cancer.

Pharmacol Res. 2016 Nov;113(Pt A):18-37

Authors: Druzhyna N, Szczesny B, Olah G, Módis K, Asimakopoulou A, Pavlidou A, Szoleczky P, Gerö D, Yanagi K, Törö G, López-García I, Myrianthopoulos V, Mikros E, Zatarain JR, Chao C, Papapetropoulos A, Hellmich MR, Szabo C

Abstract
Cystathionine-β-synthase (CBS) has been recently identified as a drug target for several forms of cancer. Currently no potent and selective CBS inhibitors are available. Using a composite collection of 8871 clinically used drugs and well-annotated pharmacological compounds (including the LOPAC library, the FDA Approved Drug Library, the NIH Clinical Collection, the New Prestwick Chemical Library, the US Drug Collection, the International Drug Collection, the 'Killer Plates' collection and a small custom collection of PLP-dependent enzyme inhibitors), we conducted an in vitro screen in order to identify inhibitors for CBS using a primary 7-azido-4-methylcoumarin (AzMc) screen to detect CBS-derived hydrogen sulfide (H2S) production. Initial hits were subjected to counterscreens using the methylene blue assay (a secondary assay to measure H2S production) and were assessed for their ability to quench the H2S signal produced by the H2S donor compound GYY4137. Four compounds, hexachlorophene, tannic acid, aurintricarboxylic acid and benserazide showed concentration-dependent CBS inhibitory actions without scavenging H2S released from GYY4137, identifying them as direct CBS inhibitors. Hexachlorophene (IC50: ∼60μM), tannic acid (IC50: ∼40μM) and benserazide (IC50: ∼30μM) were less potent CBS inhibitors than the two reference compounds AOAA (IC50: ∼3μM) and NSC67078 (IC50: ∼1μM), while aurintricarboxylic acid (IC50: ∼3μM) was equipotent with AOAA. The second reference compound NSC67078 not only inhibited the CBS-induced AzMC fluorescence signal (IC50: ∼1μM), but also inhibited with the GYY4137-induced AzMC fluorescence signal with (IC50 of ∼6μM) indicative of scavenging/non-specific effects. Hexachlorophene (IC50: ∼6μM), tannic acid (IC50: ∼20μM), benserazide (IC50: ∼20μM), and NSC67078 (IC50: ∼0.3μM) inhibited HCT116 colon cancer cells proliferation with greater potency than AOAA (IC50: ∼300μM). In contrast, although a CBS inhibitor in the cell-free assay, aurintricarboxylic acid failed to inhibit HCT116 proliferation at lower concentrations, and stimulated cell proliferation at 300μM. Copper-containing compounds present in the libraries, were also found to be potent inhibitors of recombinant CBS; however this activity was due to the CBS inhibitory effect of copper ions themselves. However, copper ions, up to 300μM, did not inhibit HCT116 cell proliferation. Benserazide was only a weak inhibitor of the activity of the other H2S-generating enzymes CSE and 3-MST activity (16% and 35% inhibition at 100μM, respectively) in vitro. Benserazide suppressed HCT116 mitochondrial function and inhibited proliferation of the high CBS-expressing colon cancer cell line HT29, but not the low CBS-expressing line, LoVo. The major benserazide metabolite 2,3,4-trihydroxybenzylhydrazine also inhibited CBS activity and suppressed HCT116 cell proliferation in vitro. In an in vivo study of nude mice bearing human colon cancer cell xenografts, benserazide (50mg/kg/days.q.) prevented tumor growth. In silico docking simulations showed that benserazide binds in the active site of the enzyme and reacts with the PLP cofactor by forming reversible but kinetically stable Schiff base-like adducts with the formyl moiety of pyridoxal. We conclude that benserazide inhibits CBS activity and suppresses colon cancer cell proliferation and bioenergetics in vitro, and tumor growth in vivo. Further pharmacokinetic, pharmacodynamic and preclinical animal studies are necessary to evaluate the potential of repurposing benserazide for the treatment of colorectal cancers.

PMID: 27521834 [PubMed - indexed for MEDLINE]

Repositioning compounds from cancer drug discovery to IPF: PI3K inhibition.

Thorax. 2016 08;71(8):675-6

Authors: Staab-Weijnitz CA, Eickelberg O

PMID: 27307018 [PubMed - indexed for MEDLINE]

Heparin prevents Zika virus induced-cytopathic effects in human neural progenitor cells.

Antiviral Res. 2017 Apr;140:13-17

Authors: Ghezzi S, Cooper L, Rubio A, Pagani I, Capobianchi MR, Ippolito G, Pelletier J, Meneghetti MC, Lima MA, Skidmore MA, Broccoli V, Yates EA, Vicenzi E

Abstract
The recent Zika virus (ZIKV) outbreak, which mainly affected Brazil and neighbouring states, demonstrated the paucity of information concerning the epidemiology of several flaviruses, but also highlighted the lack of available agents with which to treat such emerging diseases. Here, we show that heparin, a widely used anticoagulant, while exerting a modest inhibitory effect on Zika Virus replication, fully prevents virus-induced cell death of human neural progenitor cells (NPCs).

PMID: 28063994 [PubMed - indexed for MEDLINE]

Co-expression Network Approach Reveals Functional Similarities among Diseases Affecting Human Skeletal Muscle.

Front Physiol. 2017;8:980

Authors: Mukund K, Subramaniam S

Abstract
Diseases affecting skeletal muscle exhibit considerable heterogeneity in intensity, etiology, phenotypic manifestation and gene expression. Systems biology approaches using network theory, allows for a holistic understanding of functional similarities amongst diseases. Here we propose a co-expression based, network theoretic approach to extract functional similarities from 20 heterogeneous diseases comprising of dystrophinopathies, inflammatory myopathies, neuromuscular, and muscle metabolic diseases. Utilizing this framework we identified seven closely associated disease clusters with 20 disease pairs exhibiting significant correlation (p < 0.05). Mapping the diseases onto a human protein-protein interaction network enabled the inference of a common program of regulation underlying more than half the muscle diseases considered here and referred to as the "protein signature." Enrichment analysis of 17 protein modules identified as part of this signature revealed a statistically non-random dysregulation of muscle bioenergetic pathways and calcium homeostasis. Further, analysis of mechanistic similarities of less explored significant disease associations [such as between amyotrophic lateral sclerosis (ALS) and cerebral palsy (CP)] using a proposed "functional module" framework revealed adaptation of the calcium signaling machinery. Integrating drug-gene information into the quantitative framework highlighted the presence of therapeutic opportunities through drug repurposing for diseases affecting the skeletal muscle.

PMID: 29249983 [PubMed]

GDC-0879, a BRAFV600E Inhibitor, Protects Kidney Podocytes from Death.

Cell Chem Biol. 2017 Dec 06;:

Authors: Sieber J, Wieder N, Clark A, Reitberger M, Matan S, Schoenfelder J, Zhang J, Mandinova A, Bittker JA, Gutierrez J, Aygün O, Udeshi N, Carr S, Mundel P, Jehle AW, Greka A

Abstract
Progressive kidney diseases affect approximately 500 million people worldwide. Podocytes are terminally differentiated cells of the kidney filter, the loss of which leads to disease progression and kidney failure. To date, there are no therapies to promote podocyte survival. Drug repurposing may therefore help accelerate the development of cures in an area of tremendous unmet need. In a newly developed high-throughput screening assay of podocyte viability, we identified the BRAFV600E inhibitor GDC-0879 and the adenylate cyclase agonist forskolin as podocyte-survival-promoting compounds. GDC-0879 protects podocytes from injury through paradoxical activation of the MEK/ERK pathway. Forskolin promotes podocyte survival by attenuating protein biosynthesis. Importantly, GDC-0879 and forskolin are shown to promote podocyte survival against an array of cellular stressors. This work reveals new therapeutic targets for much needed podocyte-protective therapies and provides insights into the use of GDC-0879-like molecules for the treatment of progressive kidney diseases.

PMID: 29249695 [PubMed - as supplied by publisher]

Identification of atorvastatin for moderate to severe hidradenitis through drug repositioning using public gene expression dataset.

J Invest Dermatol. 2017 Dec 13;:

Authors: Kuo KY, Cho HG, Sarin K

PMID: 29247661 [PubMed - as supplied by publisher]

The druggable genome and support for target identification and validation in drug development.

Sci Transl Med. 2017 Mar 29;9(383):

Authors: Finan C, Gaulton A, Kruger FA, Lumbers RT, Shah T, Engmann J, Galver L, Kelley R, Karlsson A, Santos R, Overington JP, Hingorani AD, Casas JP

Abstract
Target identification (determining the correct drug targets for a disease) and target validation (demonstrating an effect of target perturbation on disease biomarkers and disease end points) are important steps in drug development. Clinically relevant associations of variants in genes encoding drug targets model the effect of modifying the same targets pharmacologically. To delineate drug development (including repurposing) opportunities arising from this paradigm, we connected complex disease- and biomarker-associated loci from genome-wide association studies to an updated set of genes encoding druggable human proteins, to agents with bioactivity against these targets, and, where there were licensed drugs, to clinical indications. We used this set of genes to inform the design of a new genotyping array, which will enable association studies of druggable genes for drug target selection and validation in human disease.

PMID: 28356508 [PubMed - indexed for MEDLINE]