Repurposing Resveratrol and Fluconazole To Modulate Human Cytochrome P450-Mediated Arachidonic Acid Metabolism.

Mol Pharm. 2016 Apr 04;13(4):1278-88

Authors: El-Sherbeni AA, El-Kadi AO

Abstract
Cytochrome P450 (P450) enzymes metabolize arachidonic acid (AA) to several biologically active epoxyeicosatrienoic acids (EETs) and hydroxyeicosatetraenoic acids (HETEs). Repurposing clinically-approved drugs could provide safe and readily available means to control EETs and HETEs levels in humans. Our aim was to determine how to significantly and selectively modulate P450-AA metabolism in humans by clinically-approved drugs. Liquid chromatography-mass spectrometry was used to determine the formation of 15 AA metabolites by human recombinant P450 enzymes, as well as human liver and kidney microsomes. CYP2C19 showed the highest EET-forming activity, while CYP1B1 and CYP2C8 showed the highest midchain HETE-forming activities. CYP1A1 and CYP4 showed the highest subterminal- and 20-HETE-forming activity, respectively. Resveratrol and fluconazole produced the most selective and significant modulation of hepatic P450-AA metabolism, comparable to investigational agents. Monte Carlo simulations showed that 90% of human population would experience a decrease by 6-22%, 16-39%, and 16-35% in 16-, 18-, and 20-HETE formation, respectively, after 2.5 g daily of resveratrol, and by 22-31% and 14-23% in 8,9- and 14,15-EET formation after 50 mg of fluconazole. In conclusion, clinically-approved drugs can provide selective and effective means to modulate P450-AA metabolism, comparable to investigational drugs. Resveratrol and fluconazole are good candidates to be repurposed as new P450-based treatments.

PMID: 26918316 [PubMed - indexed for MEDLINE]

Affordable orphan drugs: A role for not-for-profit organisations.

Br J Clin Pharmacol. 2017 Jan 20;:

Authors: Davies EH, Fulton E, Brook D, Hughes DA

Abstract
The success of the Regulation on Orphan Medicinal Products in the European Union is evidenced by the 127 orphan drugs that have had market authorisation since 2000. However the incentives aimed to stimulate research and development have had the unintended consequence of increasing drug cost, resulting in many orphan drugs not being cost-effective. Orphan drugs command an increasing share of the pharmaceutical market and account for a disproportionate amount of healthcare expenditure. Orphan drug ownership by socially motivated, not-for-profit organisations may facilitate access to more affordable orphan drugs, for the benefit of patients and healthcare systems alike. Using repurposed drugs as a paradigm, this review navigates the regulatory hurdles, describes the legal context and identifies funding opportunities, in a bid to facilitate and encourage not-for-profit organisations to lead on the development of affordable orphan drugs.

PMID: 28109021 [PubMed - as supplied by publisher]

Pharmacophore-based screening and drug repurposing exemplified on glycogen synthase kinase-3 inhibitors.

Mol Divers. 2017 Jan 21;:

Authors: Crisan L, Avram S, Pacureanu L

Abstract
The current study was conducted to elaborate a novel pharmacophore model to accurately map selective glycogen synthase kinase-3 (GSK-3) inhibitors, and perform virtual screening and drug repurposing. Pharmacophore modeling was developed using PHASE on a data set of 203 maleimides. Two benchmarking validation data sets with focus on selectivity were assembled using ChEMBL and PubChem GSK-3 confirmatory assays. A drug repurposing experiment linking pharmacophore matching with drug information originating from multiple data sources was performed. A five-point pharmacophore model was built consisting of a hydrogen bond acceptor (A), hydrogen bond donor (D), hydrophobic (H), and two rings (RR). An atom-based 3D quantitative structure-activity relationship (QSAR) model showed good correlative and satisfactory predictive abilities (training set [Formula: see text]; test set: [Formula: see text]; whole data set: stability [Formula: see text]). Virtual screening experiments revealed that selective GSK-3 inhibitors are ranked preferentially by Hypo-1, but fail to retrieve nonselective compounds. The pharmacophore and 3D QSAR models can provide assistance to design novel, potential GSK-3 inhibitors with high potency and selectivity pattern, with potential application for the treatment of GSK-3-driven diseases. A class of purine nucleoside antileukemic drugs was identified as potential inhibitor of GSK-3, suggesting the reassessment of the target range of these drugs.

PMID: 28108896 [PubMed - as supplied by publisher]

A physarum-inspired prize-collecting steiner tree approach to identify subnetworks for drug repositioning.

BMC Syst Biol. 2016 Dec 05;10(Suppl 5):128

Authors: Sun Y, Hameed PN, Verspoor K, Halgamuge S

Abstract
BACKGROUND: Drug repositioning can reduce the time, costs and risks of drug development by identifying new therapeutic effects for known drugs. It is challenging to reposition drugs as pharmacological data is large and complex. Subnetwork identification has already been used to simplify the visualization and interpretation of biological data, but it has not been applied to drug repositioning so far. In this paper, we fill this gap by proposing a new Physarum-inspired Prize-Collecting Steiner Tree algorithm to identify subnetworks for drug repositioning.
RESULTS: Drug Similarity Networks (DSN) are generated using the chemical, therapeutic, protein, and phenotype features of drugs. In DSNs, vertex prizes and edge costs represent the similarities and dissimilarities between drugs respectively, and terminals represent drugs in the cardiovascular class, as defined in the Anatomical Therapeutic Chemical classification system. A new Physarum-inspired Prize-Collecting Steiner Tree algorithm is proposed in this paper to identify subnetworks. We apply both the proposed algorithm and the widely-used GW algorithm to identify subnetworks in our 18 generated DSNs. In these DSNs, our proposed algorithm identifies subnetworks with an average Rand Index of 81.1%, while the GW algorithm can only identify subnetworks with an average Rand Index of 64.1%. We select 9 subnetworks with high Rand Index to find drug repositioning opportunities. 10 frequently occurring drugs in these subnetworks are identified as candidates to be repositioned for cardiovascular diseases.
CONCLUSIONS: We find evidence to support previous discoveries that nitroglycerin, theophylline and acarbose may be able to be repositioned for cardiovascular diseases. Moreover, we identify seven previously unknown drug candidates that also may interact with the biological cardiovascular system. These discoveries show our proposed Prize-Collecting Steiner Tree approach as a promising strategy for drug repositioning.

PMID: 28105946 [PubMed - in process]

Applications of chemogenomic library screening in drug discovery.

Nat Rev Drug Discov. 2017 Jan 20;:

Authors: Jones LH, Bunnage ME

Abstract
The allure of phenotypic screening, combined with the industry preference for target-based approaches, has prompted the development of innovative chemical biology technologies that facilitate the identification of new therapeutic targets for accelerated drug discovery. A chemogenomic library is a collection of selective small-molecule pharmacological agents, and a hit from such a set in a phenotypic screen suggests that the annotated target or targets of that pharmacological agent may be involved in perturbing the observable phenotype. In this Review, we describe opportunities for chemogenomic screening to considerably expedite the conversion of phenotypic screening projects into target-based drug discovery approaches. Other applications are explored, including drug repositioning, predictive toxicology and the discovery of novel pharmacological modalities.

PMID: 28104905 [PubMed - as supplied by publisher]

Continuous Suprascapular Nerve Block With a Perineural Catheter for Reverse Shoulder Arthroplasty Rescue Analgesia in a Patient With Severe Chronic Obstructive Pulmonary Disease.

A A Case Rep. 2016 Jul 15;7(2):37-40

Authors: Careskey M, Naidu R

Abstract
Reverse open shoulder arthroplasty requires a comprehensive analgesic plan involving regional anesthesia. The commonly performed interscalene brachial plexus blockade confers a high likelihood of diaphragmatic paralysis via phrenic nerve palsy, making this option riskier in patients with limited pulmonary reserve. Continuous blockade of the suprascapular nerve, a more distal branch of the C5 and C6 nerve roots, may be a viable alternative. We report a successful case of the use of a suprascapular nerve block with continuous programmed intermittent bolus perineural analgesia in a patient with severe chronic obstructive pulmonary disease who underwent reverse open shoulder arthroplasty.

PMID: 27258178 [PubMed - indexed for MEDLINE]

Extensions of indication throughout the drug product lifecycle: a quantitative analysis.

Drug Discov Today. 2016 Feb;21(2):348-55

Authors: Langedijk J, Whitehead CJ, Slijkerman DS, Leufkens HG, Schutjens MH, Mantel-Teeuwisse AK

Abstract
The marketing authorisation of the first generic product version is an important moment in a drug product lifecycle. The subsequently changed intellectual property protection prospects could affect the incentives for further drug development. We assessed the quantity and nature of extensions of indication of small molecule medicinal products authorised through the European Medicines Agency throughout the drug product lifecycle with special attention for the impact of the introduction of a first generic competitor. The majority (92.5%) of the extensions of indication was approved during the exclusivity period of the innovator product. Regulatory rethinking might be needed for a sustainable stimulation of extensions of indications in the post-generic period of a drug product lifecycle.

PMID: 26657087 [PubMed - indexed for MEDLINE]

Anthelmintic mebendazole enhances cisplatin's effect on suppressing cell proliferation and promotes differentiation of head and neck squamous cell carcinoma (HNSCC).

Oncotarget. 2017 Jan 16;:

Authors: Zhang F, Li Y, Zhang H, Huang E, Gao L, Luo W, Wei Q, Fan J, Song D, Liao J, Zou Y, Liu F, Liu J, Huang J, Guo D, Ma C, Hu X, Li L, Qu X, Chen L, Yu X, Zhang Z, Wu T, Luu HH, Haydon RC, Song J, He TC, Ji P

Abstract
Head and neck squamous cell carcinoma (HNSCC) is one of the most common and aggressive types of human cancers worldwide. Nearly a half of HNSCC patients experience recurrence within five years of treatment and develop resistance to chemotherapy. Thus, there is an urgent clinical need to develop safe and novel anticancer therapies for HNSCC. Here, we investigate the possibility of repurposing the anthelmintic drug mebendazole (MBZ) as an anti-HNSCC agent. Using the two commonly-used human HNSCC lines CAL27 and SCC15, we demonstrate MBZ exerts more potent anti-proliferation activity than cisplatin in human HNSCC cells. MBZ effectively inhibits cell proliferation, cell cycle progression and cell migration, and induces apoptosis of HNSCC cells. Mechanistically, MBZ can modulate the cancer-associated pathways including ELK1/SRF, AP1, STAT1/2, MYC/MAX, although the regulatory outcomes are context-dependent. MBZ also synergizes with cisplatin in suppressing cell proliferation and inducing apoptosis of human HNSCC cells. Furthermore, MBZ is shown to promote the terminal differentiation of CAL27 cells and keratinization of CAL27-derived xenograft tumors. Our results are the first to demonstrate that MBZ may exert its anticancer activity by inhibiting proliferation while promoting differentiation of certain HNSCC cancer cells. It's conceivable the anthelmintic drug MBZ can be repurposed as a safe and effective agent used in combination with other frontline chemotherapy drugs such as cisplatin in HNSCC treatment.

PMID: 28099902 [PubMed - as supplied by publisher]

Link prediction in drug-target interactions network using similarity indices.

BMC Bioinformatics. 2017 Jan 17;18(1):39

Authors: Lu Y, Guo Y, Korhonen A

Abstract
BACKGROUND: In silico drug-target interaction (DTI) prediction plays an integral role in drug repositioning: the discovery of new uses for existing drugs. One popular method of drug repositioning is network-based DTI prediction, which uses complex network theory to predict DTIs from a drug-target network. Currently, most network-based DTI prediction is based on machine learning - methods such as Restricted Boltzmann Machines (RBM) or Support Vector Machines (SVM). These methods require additional information about the characteristics of drugs, targets and DTIs, such as chemical structure, genome sequence, binding types, causes of interactions, etc., and do not perform satisfactorily when such information is unavailable. We propose a new, alternative method for DTI prediction that makes use of only network topology information attempting to solve this problem.
RESULTS: We compare our method for DTI prediction against the well-known RBM approach. We show that when applied to the MATADOR database, our approach based on node neighborhoods yield higher precision for high-ranking predictions than RBM when no information regarding DTI types is available.
CONCLUSION: This demonstrates that approaches purely based on network topology provide a more suitable approach to DTI prediction in the many real-life situations where little or no prior knowledge is available about the characteristics of drugs, targets, or their interactions.

PMID: 28095781 [PubMed - in process]

Emerging strategies for the treatment of pulmonary tuberculosis: promise and limitations?

Korean J Intern Med. 2016 Jan;31(1):15-29

Authors: Yew WW, Koh WJ

Abstract
A worsening scenario of drug-resistant tuberculosis has increased the need for new treatment strategies to tackle this worldwide emergency. There is a pressing need to simplify and shorten the current 6-month treatment regimen for drug-susceptible tuberculosis. Rifamycins and fluoroquinolones, as well as several new drugs, are potential candidates under evaluation. At the same time, treatment outcomes of patients with drug-resistant tuberculosis should be improved through optimizing the use of fluoroquinolones, repurposed agents and newly developed drugs. In this context, the safety and tolerance of new therapeutic approaches must be addressed.

PMID: 26767853 [PubMed - indexed for MEDLINE]

A current perspective on the oncopreventive and oncolytic properties of selective serotonin reuptake inhibitors.

Biomed Pharmacother. 2017 Jan 11;87:636-639

Authors: Radin DP, Patel P

Abstract
Current cancer research strongly focuses on identifying novel pathways that can be selectively exploited in the clinic and identifying drugs capable of exploiting cancer vulnerabilities. Occasionally, drugs identified to exploit a cancer-specific vulnerability are on the market for clinical indications in another disease area. Rebranding them as anti-cancer drugs is a process commonly referred to as drug repurposing and is typically a faster method than bringing a novel drug to market. Selective serotonin reuptake inhibitors (SSRIs) are primarily used for treating several types of depression, but over the past two decades mounting evidence suggests that drugs in this class have oncolytic properties and reduce the risk of certain cancers. In the current work, we discuss how the secondary mechanisms of action associated with these drugs mediate their oncolytic effect. In particular, sertraline limits tumor growth by abrogating the PI3K/akt signaling pathway, a growth pathway shown to be constitutively active in multiple cancers. Fluoxetine has been shown to activate the AMPA-type glutamate receptor, induce massive calcium influx and mitochondrial calcium overload and induce caspase-9-dependent apoptosis. This receptor being highly overexpressed in cancer stem cells may explain why SSRIs lower the risk of multiple types of cancer. Fluoxetine has also been shown to inhibit multidrug resistance pumps, increasing the efficacy of several standard chemotherapies. Given the vast potential of SSRIs in treating cancer, these drugs should be more heavily used not only in treating cancer-related depression, but in combating cancer and increasing the efficacy of standard of care chemotherapies.

PMID: 28088112 [PubMed - as supplied by publisher]

Identification of Febuxostat as a New Strong ABCG2 Inhibitor: Potential Applications and Risks in Clinical Situations.

Front Pharmacol. 2016;7:518

Authors: Miyata H, Takada T, Toyoda Y, Matsuo H, Ichida K, Suzuki H

Abstract
ATP-binding cassette transporter G2 (ABCG2) is a plasma membrane protein that regulates the pharmacokinetics of a variety of drugs and serum uric acid (SUA) levels in humans. Despite the pharmacological and physiological importance of this transporter, there is no clinically available drug that modulates ABCG2 function. Therefore, to identify such drugs, we investigated the effect of drugs that affect SUA levels on ABCG2 function. This strategy was based on the hypothesis that the changes of SUA levels might caused by interaction with ABCG2 since it is a physiologically important urate transporter. The results of the in vitro screening showed that 10 of 25 drugs investigated strongly inhibited the urate transport activity of ABCG2. Moreover, febuxostat was revealed to be the most promising candidate of all the potential ABCG2 inhibitors based on its potent inhibition at clinical concentrations; the half-maximal inhibitory concentration of febuxostat was lower than its maximum plasma unbound concentrations reported. Indeed, our in vivo study demonstrated that orally administered febuxostat inhibited the intestinal Abcg2 and, thereby, increased the intestinal absorption of an ABCG2 substrate sulfasalazine in wild-type mice, but not in Abcg2 knockout mice. These results suggest that febuxostat might inhibit human ABCG2 at a clinical dose. Furthermore, the results of this study lead to a proposed new application of febuxostat for enhancing the bioavailability of ABCG2 substrate drugs, named febuxostat-boosted therapy, and also imply the potential risk of adverse effects by drug-drug interactions that could occur between febuxostat and ABCG2 substrate drugs.

PMID: 28082903 [PubMed - in process]

Targeting nasopharyngeal carcinoma by artesunate through inhibiting Akt/mTOR and inducing oxidative stress.

Fundam Clin Pharmacol. 2017 Jan 11;:

Authors: Li Q, Ni W, Deng Z, Liu M, She L, Xie Q

Abstract
Drug repurposing has become an alternative therapeutic strategy for cancer treatment given the known pharmacokinetics and toxicity. The inhibitory effects of artesunate have been reported in various cancers. In this work, we investigated the effects of artesunate in nasopharyngeal carcinoma (NPC). We demonstrate that artesunate significantly inhibits proliferation via arresting NPC cells at G2/M phase. It also induces apoptosis through caspase-dependent and mitochondria-independent pathways in multiple NPC cell lines. The combination of artesunate and cisplatin is synergistic in targeting NPC cells in in vitro cellular culture system and in vivo xenograft tumor models. Artesunate inhibits phosphorylation of essential molecules involved in Akt/mTOR pathway in NPC cells, such as Akt, mTOR and 4EBP1, and its inhibitory effects are partially abolished by overexpression of constitutively active Akt. In addition, artesunate also induces mitochondrial dysfunction and oxidative stress via inhibiting mitochondrial respiration, increasing levels of mitochondrial superoxide and cellular ROS, leading to decreased ATP levels. Two ROS scavengers partially abolish the inhibitory effects of artesunate in NPC cells. These data suggest that both inhibition of Akt/mTOR pathway and induction of reactive oxygen species (ROS) are required for the action of artesunate in NPC cells. Our work demonstrates that artesunate is a potential candidate for NPC treatment. Our work also highlights the critical roles of Akt/mTOR pathway and mitochondrial function in NPC cells. This article is protected by copyright. All rights reserved.

PMID: 28078787 [PubMed - as supplied by publisher]

Correction: A Network-Based Data Integration Approach to Support Drug Repurposing and Multi-Target Therapies in Triple Negative Breast Cancer.

PLoS One. 2017;12(1):e0170363

Authors: Vitali F, Cohen LD, Demartini A, Amato A, Eterno V, Zambelli A, Bellazzi R

Abstract
[This corrects the article DOI: 10.1371/journal.pone.0162407.].

PMID: 28076436 [PubMed - in process]

Construction of an miRNA-regulated drug-pathway network reveals drug repurposing candidates for myasthenia gravis.

Int J Mol Med. 2017 Jan 11;:

Authors: Cao Y, Lu X, Wang J, Zhang H, Liu Z, Xu S, Wang T, Ning S, Xiao B, Wang L

Abstract
Myasthenia gravis (MG) is a rare debilitating autoimmune neuromuscular disorder. Many studies have focused on the mechanism and treatment strategies of MG. However, the exact pathogenesis of MG and effective treatment strategies remain unclear. Recent studies have indicated that microRNAs (miRNAs or miRs) can regulate the pathological pathways of MG, suggesting their potential role in novel treatments. In the present study, we created a comprehensive catalog of experimentally confirmed MG risk genes and miRNAs by manually mining published literature and public databases. Based on these genes and miRNAs, we identified 41 MG risk pathways and 105 approved drugs that can affect these pathways. Some important MG-related pathways, such as hsa04060 (cytokine-cytokine receptor interaction) and hsa05200 (pathway in cancer), were found to be regulated by MG risk miRNAs and drugs. Furthermore, we constructed an miRNA-regulated drug-pathway network and identified miRNAs and drugs that synergistically regulate key MG pathways and biological processes. We developed a drug repurposing strategy to identify 25 drug repurposing candidates for MG; several of these drugs, such as rituximab, adalimumab, sunitinib, and muromonab, have the potential to be novel MG treatment drugs. This study provides novel insight into the pathogenesis of MG and potential drug candidates for MG were identified.

PMID: 28075449 [PubMed - as supplied by publisher]

A review of connectivity map and computational approaches in pharmacogenomics.

Brief Bioinform. 2017 Jan 09;:

Authors: Musa A, Ghoraie LS, Zhang SD, Galzko G, Yli-Harja O, Dehmer M, Haibe-Kains B, Emmert-Streib F

Abstract
Large-scale perturbation databases, such as Connectivity Map (CMap) or Library of Integrated Network-based Cellular Signatures (LINCS), provide enormous opportunities for computational pharmacogenomics and drug design. A reason for this is that in contrast to classical pharmacology focusing at one target at a time, the transcriptomics profiles provided by CMap and LINCS open the door for systems biology approaches on the pathway and network level. In this article, we provide a review of recent developments in computational pharmacogenomics with respect to CMap and LINCS and related applications.

PMID: 28069634 [PubMed - as supplied by publisher]

Computational Polypharmacology: a New Paradigm for Drug Discovery.

Expert Opin Drug Discov. 2017 Jan 08;:

Authors: Chaudhari R, Tan Z, Huang B, Zhang S

PMID: 28067061 [PubMed - as supplied by publisher]

DockingApp: a user friendly interface for facilitated docking simulations with AutoDock Vina.

J Comput Aided Mol Des. 2017 Jan 06;:

Authors: Di Muzio E, Toti D, Polticelli F

Abstract
Molecular docking is a powerful technique that helps uncover the structural and energetic bases of the interaction between macromolecules and substrates, endogenous and exogenous ligands, and inhibitors. Moreover, this technique plays a pivotal role in accelerating the screening of large libraries of compounds for drug development purposes. The need to promote community-driven drug development efforts, especially as far as neglected diseases are concerned, calls for user-friendly tools to allow non-expert users to exploit the full potential of molecular docking. Along this path, here is described the implementation of DockingApp, a freely available, extremely user-friendly, platform-independent application for performing docking simulations and virtual screening tasks using AutoDock Vina. DockingApp sports an intuitive graphical user interface which greatly facilitates both the input phase and the analysis of the results, which can be visualized in graphical form using the embedded JMol applet. The application comes with the DrugBank set of more than 1400 ready-to-dock, FDA-approved drugs, to facilitate virtual screening and drug repurposing initiatives. Furthermore, other databases of compounds such as ZINC, available also in AutoDock format, can be readily and easily plugged in.

PMID: 28063067 [PubMed - as supplied by publisher]

Drug Repurposing Hypothesis Generation Using the "RE:fine Drugs" System.

J Vis Exp. 2016 Dec 11;(118):

Authors: Regan K, Moosavinasab S, Payne P, Lin S

Abstract
The promise of drug repurposing is that existing drugs may be used for new disease indications in order to curb the high costs and time for approval. The goal of computational methods for drug repurposing is to enable solutions for safer, cheaper and faster drug discovery. Towards this end, we developed a novel method that integrates genetic and clinical phenotype data from large-scale GWAS and PheWAS studies with detailed drug information on the concept of transitive Drug-Gene-Disease triads. We created "RE:fine Drugs," a freely available, interactive dashboard that automates gene, disease and drug-based searches to identify drug repurposing candidates. This web-based tool supports a user-friendly interface that includes an array of advanced search and export options. Results can be prioritized in a variety of ways, including but not limited to, biomedical literature support, strength and statistical significance of GWAS and/or PheWAS associations, disease indications and molecular drug targets. Here we provide a protocol that illustrates the functionalities available in the "RE:fine Drugs" system and explores the different advanced options through a case study.

PMID: 28060329 [PubMed - in process]

Predicting High-Impact Pharmacological Targets by Integrating Transcriptome and Text-Mining Features.

J Pharm Pharm Sci. 2016 Oct - Dec;19(4):475-495

Authors: Mayburd A, Baranova A

Abstract
PURPOSE: Novel, "outside of the box" approaches are needed for evaluating candidate molecules, especially in oncology. Throughout the years of 2000-2010, the efficiency of drug development fell to barely acceptable levels, and in the second decade of this century, levels have improved only marginally. This dismal condition continues despite unprecedented progress in the development of a variety of high-throughput tools, computational methods, aggregated databases, drug repurposing programs and innovative chemistries. Here we tested a hypothesis that the economic impact of targeting a particular gene product is predictable a priori by employing a combination of transcriptome profiles and quantitative metrics reflecting existing literature.
METHODS: To extract classification features, the gene expression patterns of a posteriori high-impact and low-impact anti-cancer target sets were compared. To minimize the possible bias of text-mining, the number of manuscripts published prior to the first clinical trial or relevant review paper, as well as its first derivative in this interval, were collected and used as quantitative metrics of public interest.
RESULTS: By combining the gene expression and literature mining features, a 4-fold enrichment in high-impact targets was produced, resulting in a favourable ROC curve analysis for the top impact targets. The dataset was enriched by the highest impact anti-cancer targets, while demonstrating drastic differences in economic value between high and low-impact targets. Known anti-cancer products of EGFR, ERBB2, CYP19A1/aromatase, MTOR, PTGS2, tubulin, VEGFA, BRAF, PGR, PDGFRA, SRC, REN, CSF1R, CTLA4 and HSP90AA1 genes received the highest scores for predicted impact, while microsomal steroid sulfatase, anticoagulant protein C, p53, CDKN2A, c-Jun, and TNSFS11 were highlighted as most promising research-stage targets.
CONCLUSIONS: A significant cost reduction may be achieved by a priori impact assessment of targets and ligands before their development or repurposing. Expanding a suite of combinational treatments could also decrease the costs, while achieving a higher impact per developed ligand. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

PMID: 28057171 [PubMed - in process]