Chemoproteomics-driven drug discovery: addressing high attrition rates.


:The advent of multiple high-throughput technologies has brought drug discovery round almost full circle, from pharmacological testing of compounds in vivo to engineered molecular target assays and back to integrated phenotypic screens in cells and organisms. In the past, primary screens to identify new pharmacological agents involved administering compounds to an animal and monitoring a pharmacologic endpoint. For example, antihypertensive agents were identified by dosing spontaneously hypertensive rats with compounds and observing whether their blood pressure dropped. In taking this phenomenological approach, scientists were focused on the final goal, in this example lowering of blood pressure, rather than developing an understanding of the target, or targets, the compounds were impacting. With the evolution of rational target-based approaches, scientists were able to study the direct interaction of compounds with their intended targets, expecting that this would lead to more-selective and safer therapeutics. With the industrialization of screening, referred to as HTS, hundreds of thousands of compounds were screened in robot-driven assays against targets of interest (with this goal in mind). However, an unintentional outcome of the migration from in vivo primary screens to highly target-specific HTS assays was a reduction in biological context caused by the separation of the target from other cellular proteins and processes that might impact its function. Recognition of the potential consequences of this over-simplification drove the modification of HTS processes and equipment to be compatible with cellular assays.


Drug Discov Today


Drug discovery today


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2006-06-01 00:00:00














  • Drug-induced liver injury severity and toxicity (DILIst): binary classification of 1279 drugs by human hepatotoxicity.

    abstract::Drug-induced liver injury (DILI) is of significant concern to drug development and regulatory review because of the limited success with existing preclinical models. For developing alternative methods, a large drug list is needed with known DILI severity and toxicity. We augmented the DILIrank data set [annotated usin...

    journal_title:Drug discovery today

    pub_type: 杂志文章,评审


    authors: Thakkar S,Li T,Liu Z,Wu L,Roberts R,Tong W

    更新日期:2020-01-01 00:00:00

  • A challenging drug development process in the era of personalized medicine.

    abstract::After years of hesitation a larger number of pharmaceutical and biotech companies are now supporting the idea of a more individualized pharmacotherapy. The companies that are now involved in this research-demanding area will have to face several challenges. The key factor for success will be an in-depth molecular unde...

    journal_title:Drug discovery today

    pub_type: 杂志文章,评审


    authors: Jørgensen JT

    更新日期:2011-10-01 00:00:00

  • Designed covalent allosteric modulators: an emerging paradigm in drug discovery.

    abstract::Covalent allosteric modulators possess the pharmacological advantages (high potency, extended duration of action and low drug resistance) of covalent ligands and the additional benefit of the higher specificity and lower toxicity of allosteric modulators. This approach is gaining increasing recognition as a valuable t...

    journal_title:Drug discovery today

    pub_type: 杂志文章,评审


    authors: Lu S,Zhang J

    更新日期:2017-02-01 00:00:00

  • New perspectives in oral peptide delivery.

    abstract::Owing to their structural diversity, peptides are a unique source of innovative active ingredients. However, their development has been challenging because of their disadvantageous pharmacokinetic (PK) properties. Over the past decade, many attempts have been made to improve the oral bioavailability of peptide drugs. ...

    journal_title:Drug discovery today

    pub_type: 杂志文章,评审


    authors: Zizzari AT,Pliatsika D,Gall FM,Fischer T,Riedl R

    更新日期:2021-01-23 00:00:00

  • Pharmaceutical patents: reconciling the human right to health with the incentive to invent.

    abstract::In developed countries that protect core aspects of the fundamental human right to the highest attainable standard of health, how does that right intersect with intellectual property rights? Here, the human rights implication of providing access to all cancer drugs recommended by experts in a developed country is cons...

    journal_title:Drug discovery today

    pub_type: 杂志文章


    authors: Khachigian LM

    更新日期:2020-07-01 00:00:00

  • Drug-target identification in Drosophila cells: combining high-throughout RNAi and small-molecule screens.

    abstract::RNA interference (RNAi) and small-molecule approaches are synergistic on multiple levels, from technology and high-throughput screen development to target identification and functional studies. Here, we describe the RNAi screening platform that we have established and made available to the community through the Drosop...

    journal_title:Drug discovery today

    pub_type: 杂志文章,评审


    authors: Perrimon N,Friedman A,Mathey-Prevot B,Eggert US

    更新日期:2007-01-01 00:00:00

  • Chronic autoimmune-mediated inflammation: a senescent immune response to injury.

    abstract::The increasing prevalence of chronic autoimmune-mediated inflammatory diseases (AIMIDs) in ageing western societies is a major challenge for the drug development industry. The current high medical need for more-effective treatments is at least in part caused by our limited understanding of the mechanisms that drive ch...

    journal_title:Drug discovery today

    pub_type: 杂志文章,评审


    authors: 't Hart BA,Chalan P,Koopman G,Boots AM

    更新日期:2013-04-01 00:00:00

  • Accelerated drug discovery by rapid candidate drug identification.

    abstract::The eventual candidate drug (CD) is often already synthesized during early drug discovery but not nominated until much later. To facilitate the rapid identification of a potential CD, a thoroughly worked-out CD target profile (CDTP) with criteria acceptable for the disease target product profile (TPP) is required at t...

    journal_title:Drug discovery today

    pub_type: 杂志文章


    authors: Bergström F,Lindmark B

    更新日期:2019-06-01 00:00:00

  • Regeneration of stalled immune responses to transformed and infected cells using γδ T cells.

    abstract::Manipulation of the human immune system is becoming more of a therapeutic focus as a treatment option or complement. Prominent examples are the increasing use of monoclonal antibodies in combating malignant tumours, and the numerous adoptive immunotherapy trials underway. One important aspect of any use of the human i...

    journal_title:Drug discovery today

    pub_type: 杂志文章,评审


    authors: Gustafsson K,Anderson J,Fisher JPH,Yan M

    更新日期:2014-06-01 00:00:00

  • Four disruptive strategies for removing drug discovery bottlenecks.

    abstract::Drug discovery is shifting focus from industry to outside partners and, in the process, creating new bottlenecks. Technologies like high throughput screening (HTS) have moved to a larger number of academic and institutional laboratories in the USA, with little coordination or consideration of the outputs and creating ...

    journal_title:Drug discovery today

    pub_type: 杂志文章


    authors: Ekins S,Waller CL,Bradley MP,Clark AM,Williams AJ

    更新日期:2013-03-01 00:00:00

  • In silico platform for xenobiotics ADME-T pharmacological properties modeling and prediction. Part II: The body in a Hilbertian space.

    abstract::We have broken old surviving dogmas and concepts used in computational chemistry and created an efficient in silico ADME-T pharmacological properties modeling and prediction toolbox for any xenobiotic. With the help of an innovative and pragmatic approach combining various in silico techniques, like molecular modeling...

    journal_title:Drug discovery today

    pub_type: 杂志文章,评审


    authors: Jacob A,Pratuangdejkul J,Buffet S,Launay JM,Manivet P

    更新日期:2009-04-01 00:00:00

  • Market entry, power, pharmacokinetics: what makes a successful drug innovation?

    abstract::Depending on the timing of market entry, radical innovations can be distinguished from incremental innovations. Whereas a radical innovation typically is the first available derivative of a drug class, incremental innovations are launched later and show a certain benefit compared with the radical innovation. Here, we ...

    journal_title:Drug discovery today

    pub_type: 杂志文章,评审


    authors: Alt S,Helmstädter A

    更新日期:2018-02-01 00:00:00

  • Organoid-on-a-chip and body-on-a-chip systems for drug screening and disease modeling.

    abstract::In recent years, advances in tissue engineering and microfabrication technologies have enabled rapid growth in the areas of in vitro organoid development as well as organoid-on-a-chip platforms. These 3D model systems often are able to mimic human physiology more accurately than traditional 2D cultures and animal mode...

    journal_title:Drug discovery today

    pub_type: 杂志文章,评审


    authors: Skardal A,Shupe T,Atala A

    更新日期:2016-09-01 00:00:00

  • Gastric bypass surgery mimetic approaches.

    abstract::Gastric bypass surgery is effectively a polypharmacological approach for treatment of obesity, type 2 diabetes and nonalcoholic steatohepatitis (NASH). The gastric bypass mimetic approaches reviewed are fixed-dose combinatorial pharmacological approaches. There are two key concepts incorporated into these gastric bypa...

    journal_title:Drug discovery today

    pub_type: 杂志文章,评审


    authors: Boettcher BR

    更新日期:2017-08-01 00:00:00

  • Gestational hypoxia and epigenetic programming of brain development disorders.

    abstract::Adverse environmental conditions faced by an individual early during its life, such as gestational hypoxia, can have a profound influence on the risk of diseases, such as neurological disorders, in later life. Clinical and preclinical studies suggest that epigenetic programming of gene expression patterns in response ...

    journal_title:Drug discovery today

    pub_type: 杂志文章,评审


    authors: Ma Q,Xiong F,Zhang L

    更新日期:2014-12-01 00:00:00

  • Understanding autoimmune disease: new targets for drug discovery.

    abstract::A more complete understanding of the mechanisms that drive autoimmune diseases has begun to be translated into therapeutic options with significant clinical consequences. A clear example of this is the introduction of biological therapies, which have provided new therapeutic avenues, as well as validated the mediators...

    journal_title:Drug discovery today

    pub_type: 杂志文章,评审


    authors: Balagué C,Kunkel SL,Godessart N

    更新日期:2009-10-01 00:00:00

  • Applying genetics in inflammatory disease drug discovery.

    abstract::Recent groundbreaking work in genetics has identified thousands of small-effect genetic variants throughout the genome that are associated with almost all major diseases. These genome-wide association studies (GWAS) are often proposed as a source of future medical breakthroughs. However, with several notable exception...

    journal_title:Drug discovery today

    pub_type: 杂志文章


    authors: Folkersen L,Biswas S,Frederiksen KS,Keller P,Fox B,Fleckner J

    更新日期:2015-10-01 00:00:00

  • Nano-engineered delivery systems for cancer imaging and therapy: Recent advances, future direction and patent evaluation.

    abstract::Cancer is the second highest cause of death worldwide. Several therapeutic approaches, such as conventional chemotherapy, antibodies and small molecule inhibitors and nanotherapeutics have been employed in battling cancer. Amongst them, nanotheranostics is an example of successful personalized medicine bearing dual ro...

    journal_title:Drug discovery today

    pub_type: 杂志文章,评审


    authors: Nabil G,Bhise K,Sau S,Atef M,El-Banna HA,Iyer AK

    更新日期:2019-02-01 00:00:00

  • Can BDDCS illuminate targets in drug design?

    abstract::The fact that pharmacokinetic (PK) properties of drugs influence their interaction with protein targets is a principle known for decades. The same cannot be said for the opposite, namely that targets influence the PK properties of drugs. Evidence confirming this possibility is introduced here for the first time, as we...

    journal_title:Drug discovery today

    pub_type: 杂志文章,评审


    authors: Bocci G,Benet LZ,Oprea TI

    更新日期:2019-12-01 00:00:00

  • Monoclonal antibodies for chronic refractory asthma and pipeline developments.

    abstract::Patients with severe asthma suffer persistent symptoms and/or frequent exacerbations despite high-intensity treatment. Their severe unrelenting symptoms have a huge impact on healthcare resources owing to frequent hospital admissions and requirement for intensive treatments. Consequently, there is an undeniable need f...

    journal_title:Drug discovery today

    pub_type: 杂志文章,评审


    authors: Polosa R,Casale T

    更新日期:2012-06-01 00:00:00

  • Translational dermatology in drug discovery: perspectives for integrating humanized xenograft models and experimental clinical studies.

    abstract::Application of humanized xenotransplantation disease models and experimental clinical studies in the context of translational research in drug discovery in dermatology is an opportunity to reduce failure due to lack of efficacy in clinical development stage. ...

    journal_title:Drug discovery today

    pub_type: 杂志文章,评审


    authors: Petersen TK,Sørensen P

    更新日期:2008-03-01 00:00:00

  • Filtering promiscuous compounds in early drug discovery: is it a good idea?

    abstract::The use of computational filters for excluding supposedly nonspecific and promiscuous compounds from chemical libraries is a controversial issue, because many drugs used in clinics today would never reach the market if these filters were applied. In part, this conflict could be caused by the paradigm: one-drug-one-tar...

    journal_title:Drug discovery today

    pub_type: 杂志文章


    authors: Senger MR,Fraga CA,Dantas RF,Silva FP Jr

    更新日期:2016-06-01 00:00:00

  • Computational chemistry-driven decision making in lead generation.

    abstract::Novel starting points for drug discovery projects are generally found either by screening large collections of compounds or smaller more-focused libraries. Ideally, hundreds or even thousands of actives are initially found, and these need to be reduced to a handful of promising lead series. In several sequential steps...

    journal_title:Drug discovery today

    pub_type: 杂志文章,评审


    authors: Schnecke V,Boström J

    更新日期:2006-01-01 00:00:00

  • Organometallic compounds in oncology: implications of novel organotins as antitumor agents.

    abstract::Since the introduction of cisplatin in cancer therapy, metal complexes and organometallic compounds have been gaining growing importance in oncology. The impressive clinical effectiveness of cisplatin is limited by significant side effects and the emergence of drug resistance. Thus, novel classic and unconventional Pt...

    journal_title:Drug discovery today

    pub_type: 杂志文章,评审


    authors: Alama A,Tasso B,Novelli F,Sparatore F

    更新日期:2009-05-01 00:00:00

  • New ways to treat bacterial infections.

    abstract::There is an urgent need for fresh approaches to the treatment of bacterial infections because of the changing patterns of infectious disease and the emergence of bacterial strains resistant to current antibiotics. Modification of the cell phenotype to sensitize bacteria to components of the hosts' immune system or to ...

    journal_title:Drug discovery today

    pub_type: 杂志文章,评审


    authors: Taylor PW,Stapleton PD,Paul Luzio J

    更新日期:2002-11-01 00:00:00

  • Memo to the FDA and ICH: appeal for in vivo drug target identification and target pharmacokinetics Recommendations for improved procedures and requirements.

    abstract::This memorandum is addressed to members of regulatory agencies, as well as managers of pharmaceutical companies. Pharmacokineticists and toxicologists may consider this proposal, weigh its merits, and provide input for implementation. Experience from academic research and ADME experiments during drug development has p...

    journal_title:Drug discovery today

    pub_type: 杂志文章,评审


    authors: Stumpf WE

    更新日期:2007-08-01 00:00:00

  • Poetry and verse: an ideal medium for scientific communication?

    abstract::'Many professional scientists over the years have expressed their thoughts and ideas in poetry.' ...

    journal_title:Drug discovery today

    pub_type: 杂志文章


    authors: Rowe RC

    更新日期:2000-10-01 00:00:00

  • DNA-nanorobot-guided thrombin-inducing tumor infarction: raising new potential clinical concerns.

    abstract::DNA-nanorobot-guided thrombin-inducing tumor infarction (DNA NanorobotTh-ITI) is emerging as a powerful therapeutic strategy for treatment of solid cancers. The technology represents a major advance in the application of DNA nanotechnology for anticancer therapy. More importantly, the technology is being translated fr...

    journal_title:Drug discovery today

    pub_type: 杂志文章


    authors: Zheng K,Kros JM,Li J,Zheng PP

    更新日期:2020-06-01 00:00:00

  • Targeting cancer-initiating cell drug-resistance: a roadmap to a new-generation of cancer therapies?

    abstract::The occurrence of drug resistance in oncology accounts for treatment failure and relapse of diverse tumor types. Cancers contain cells at various stages of differentiation together with a limited number of 'cancer-initiating cells' able to self-renew and divide asymmetrically, driving tumorigenesis. Cancer-initiating ...

    journal_title:Drug discovery today

    pub_type: 杂志文章,评审


    authors: Alama A,Orengo AM,Ferrini S,Gangemi R

    更新日期:2012-05-01 00:00:00

  • Cell microarrays in drug discovery.

    abstract::There is an increasing need for systematic cell-based assays in a high-throughput screening (HTS) format to analyze the phenotypic consequences of perturbing mammalian cells with drugs, genes, interfering RNA. Taking advantage of the recent progress in microtechnology, new cell microarrays are being developed and appl...

    journal_title:Drug discovery today

    pub_type: 杂志文章,评审


    authors: Castel D,Pitaval A,Debily MA,Gidrol X

    更新日期:2006-07-01 00:00:00