A Chemocentric Approach to the Identification of Cancer Targets

Flachner, Beáta; Lőrincz, Zsolt; Carotti, Angelo; Nicolotti, Orazio; Kuchipudi, Praveena; Remez, Nikita; Sanz, Ferrán; Tóvári, József; Szabo, Miklos J.; Bertók, Béla; Cseh, Sándor; Mestres, Jordi; Dormán, György

doi:10.1371/journal.pone.0035582

Cited by 19 publications

(18 citation statements)

References 57 publications

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“…The method has been successfully validated retrospectively, on its ability to predict the entire experimental interaction matrix between 13 antipsychotic drugs and 34 protein targets [67] and to identify cancer-relevant targets from selective cytotoxic compounds in tumour cells [68], but also prospectively, on its capacity to identify the correct targets for all molecules contained in a biologically-orphan chemical library [69], to correctly anticipate the affinity profile of the drug cyclobenzaprine [70], to identify a confounding off-target of a widely used chemical probe [71], and to predict the target of novel inhibitors of amyloid β-induced neuronal apoptosis [72].…”

Section: Methodsmentioning

confidence: 99%

Prediction of the P. falciparum Target Space Relevant to Malaria Drug Discovery

Spitzmüller

Mestres

2013

PLoS Comput Biol

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Malaria is still one of the most devastating infectious diseases, affecting hundreds of millions of patients worldwide. Even though there are several established drugs in clinical use for malaria treatment, there is an urgent need for new drugs acting through novel mechanisms of action due to the rapid development of resistance. Resistance emerges when the parasite manages to mutate the sequence of the drug targets to the extent that the protein can still perform its function in the parasite but can no longer be inhibited by the drug, which then becomes almost ineffective. The design of a new generation of malaria drugs targeting multiple essential proteins would make it more difficult for the parasite to develop full resistance without lethally disrupting some of its vital functions. The challenge is then to identify which set of Plasmodium falciparum proteins, among the millions of possible combinations, can be targeted at the same time by a given chemotype. To do that, we predicted first the targets of the close to 20,000 antimalarial hits identified recently in three independent phenotypic screening campaigns. All targets predicted were then projected onto the genome of P. falciparum using orthologous relationships. A total of 226 P. falciparum proteins were predicted to be hit by at least one compound, of which 39 were found to be significantly enriched by the presence and degree of affinity of phenotypically active compounds. The analysis of the chemically compatible target combinations containing at least one of those 39 targets led to the identification of a priority set of 64 multi-target profiles that can set the ground for a new generation of more robust malaria drugs.

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Section: Methodsmentioning

confidence: 99%

Prediction of the P. falciparum Target Space Relevant to Malaria Drug Discovery

Spitzmüller

Mestres

2013

PLoS Comput Biol

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“…The method has been successfully validated retrospectively on its ability to predict the entire experimental interaction matrix between 13 antipsychotic drugs and 34 protein targets24 and to identify cancer‐relevant targets from selective cytotoxic compounds in tumor cells 25. It also served in prospective studies, by its capacity to identify the correct targets for all molecules contained in a biologically orphan chemical library,26 to correctly anticipate the affinity profile of the drug cyclobenzaprine,27 to identify a confounding off‐target of a widely used chemical probe,28 and to predict the target of novel inhibitors of amyloid‐induced neuronal apoptosis 29…”

Section: Methodsmentioning

confidence: 99%

Design of a General‐Purpose European Compound Screening Library for EU‐OPENSCREEN

et al. 2014

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This work describes a collaborative effort to define and apply a protocol for the rational selection of a general-purpose screening library, to be used by the screening platforms affiliated with the EU-OPENSCREEN initiative. It is designed as a standard source of compounds for primary screening against novel biological targets, at the request of research partners. Given the general nature of the potential applications of this compound collection, the focus of the selection strategy lies on ensuring chemical stability, absence of reactive compounds, screening-compliant physicochemical properties, loose compliance to drug-likeness criteria (as drug design is a major, but not exclusive application), and maximal diversity/coverage of chemical space, aimed at providing hits for a wide spectrum of drugable targets. Finally, practical availability/cost issues cannot be avoided. The main goal of this publication is to inform potential future users of this library about its conception, sources, and characteristics. The outline of the selection procedure, notably of the filtering rules designed by a large committee of European medicinal chemists and chemoinformaticians, may be of general methodological interest for the screening/medicinal chemistry community. The selection task of 200K molecules out of a pre-filtered set of 1.4M candidates was shared by five independent European research groups, each picking a subset of 40K compounds according to their own in-house methodology and expertise. An in-depth analysis of chemical space coverage of the library serves not only to characterize the collection, but also to compare the various chemoinformatics-driven selection procedures of maximal diversity sets. Compound selections contributed by various participating groups were mapped onto general-purpose self-organizing maps (SOMs) built on the basis of marketed drugs and bioactive reference molecules. In this way, the occupancy of chemical space by the EU-OPENSCREEN library could be directly compared with distributions of known bioactives of various classes. This mapping highlights the relevance of the selection and shows how the consensus reached by merging the five different 40K selections contributes to achieve this relevance. The approach also allows one to readily identify subsets of target- or target-class-oriented compounds from the EU-OPENSCREEN library to suit the needs of the diverse range of potential users. The final EU-OPENSCREEN library, assembled by merging five independent selections of 40K compounds from various expert groups, represents an excellent example of a Europe-wide collaborative effort toward the common objective of building best-in-class European open screening platforms.

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“…For example, it is widely accepted that class A aminergic G protein-coupled receptors (GPCRs) are closely associated with diseases of the central nervous system [27]. However, members of this GPCR subclass play a role in cardiovascular diseases [28] and oncology [29] as well.…”

Section: Which Therapeutic Areas?mentioning

confidence: 99%

Drug Repurposing: Far Beyond New Targets for Old Drugs

Oprea

Mestres

2012

AAPS J

231

138

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Abstract. Repurposing drugs requires finding novel therapeutic indications compared to the ones for which they were already approved. This is an increasingly utilized strategy for finding novel medicines, one that capitalizes on previous investments while derisking clinical activities. This approach is of interest primarily because we continue to face significant gaps in the drug-target interactions matrix and to accumulate safety and efficacy data during clinical studies. Collecting and making publicly available as much data as possible on the target profile of drugs offer opportunities for drug repurposing, but may limit the commercial applications by patent applications. Certain clinical applications may be more feasible for repurposing than others because of marked differences in side effect tolerance. Other factors that ought to be considered when assessing drug repurposing opportunities include relevance to the disease in question and the intellectual property landscape. These activities go far beyond the identification of new targets for old drugs.KEY WORDS: drug repurposing; drug-target interactions; intellectual property; side effect tolerance; target identification.There are two major "unknown unknown" categories in drug discovery [1] that can be linked to the main reasons for failure in drug approval, namely safety and efficacy [2]. The first category is related to the toxicological and pharmacokinetic profiles of the new molecular entity (NME), and it is mainly addressed in phases I and IIa clinical trials, following multiple preclinical evaluations: these evaluate the therapeutic regimen (i.e., dose and frequency) and safety aspects concerned to the NME. The second category relates to the protein target and biological pathway that are subject to therapeutic interference, and it is indirectly linked to the clinical efficacy of the NME under investigation: in this case, the question being addressed is whether the NME-induced perturbation of the chosen (hypothesized) target or pathway leads to the desired clinical effect [3]. The uncertainty related to the unknown unknown aspect of discovery is often mitigated by eliminating some of the "unknown" elements: either the NME is well understood, i.e., an approved drug [4], or the target/pathway is well described, i.e., already successfully manipulated therapeutically [5]. Preferably, both "unknowns" have been addressed previously, with the expectation that derisking the discovery aspect may lead to a higher success rate.The unknown unknown strategy has been rewarding, as many blockbuster franchises have emerged following this recipe, e.g., histamine H2 antagonists, proton pump inhibitors, anticoagulant/antithrombotic therapy, or drugs to reduce hypercholesterolemia [6]. However, such drugs are the result of a long, high-cost, and high-risk optimization process, often subject to "fast followers," where first-in-class does not equate with the most financially rewarding NME [7]. In order to reduce time-to-market, as well as associated costs and risks, alternat...

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A Chemocentric Approach to the Identification of Cancer Targets

Cited by 19 publications

References 57 publications

Prediction of the P. falciparum Target Space Relevant to Malaria Drug Discovery

Prediction of the P. falciparum Target Space Relevant to Malaria Drug Discovery

Design of a General‐Purpose European Compound Screening Library for EU‐OPENSCREEN

Drug Repurposing: Far Beyond New Targets for Old Drugs

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