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Nature Reviews. Drug Discovery

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https://read.qxmd.com/read/30760888/tryptophan-metabolism-as-a-common-therapeutic-target-in-cancer-neurodegeneration-and-beyond
#1
REVIEW
Michael Platten, Ellen A A Nollen, Ute F Röhrig, Francesca Fallarino, Christiane A Opitz
L-Tryptophan (Trp) metabolism through the kynurenine pathway (KP) is involved in the regulation of immunity, neuronal function and intestinal homeostasis. Imbalances in Trp metabolism in disorders ranging from cancer to neurodegenerative disease have stimulated interest in therapeutically targeting the KP, particularly the main rate-limiting enzymes indoleamine-2,3-dioxygenase 1 (IDO1), IDO2 and tryptophan-2,3-dioxygenase (TDO) as well as kynurenine monooxygenase (KMO). However, although small-molecule IDO1 inhibitors showed promise in early-stage cancer immunotherapy clinical trials, a phase III trial was negative...
February 13, 2019: Nature Reviews. Drug Discovery
https://read.qxmd.com/read/30728472/antibodies-and-venom-peptides-new-modalities-for-ion-channels
#2
REVIEW
Heike Wulff, Palle Christophersen, Paul Colussi, K George Chandy, Vladimir Yarov-Yarovoy
Ion channels play fundamental roles in both excitable and non-excitable tissues and therefore constitute attractive drug targets for myriad neurological, cardiovascular and metabolic diseases as well as for cancer and immunomodulation. However, achieving selectivity for specific ion channel subtypes with small-molecule drugs has been challenging, and there currently is a growing trend to target ion channels with biologics. One approach is to improve the pharmacokinetics of existing or novel venom-derived peptides...
February 6, 2019: Nature Reviews. Drug Discovery
https://read.qxmd.com/read/30710128/adeno-associated-virus-vector-as-a-platform-for-gene-therapy-delivery
#3
REVIEW
Dan Wang, Phillip W L Tai, Guangping Gao
Adeno-associated virus (AAV) vectors are the leading platform for gene delivery for the treatment of a variety of human diseases. Recent advances in developing clinically desirable AAV capsids, optimizing genome designs and harnessing revolutionary biotechnologies have contributed substantially to the growth of the gene therapy field. Preclinical and clinical successes in AAV-mediated gene replacement, gene silencing and gene editing have helped AAV gain popularity as the ideal therapeutic vector, with two AAV-based therapeutics gaining regulatory approval in Europe or the United States...
February 1, 2019: Nature Reviews. Drug Discovery
https://read.qxmd.com/read/30679806/interferons-%C3%AE-and-%C3%AE-in-cancer-therapeutic-opportunities-from-new-insights
#4
REVIEW
Ernest C Borden
Over the past decade, preclinical and clinical research have confirmed the essential role of interferons for effective host immunological responses to malignant cells. Type I interferons (IFNα and IFNβ) directly regulate transcription of >100 downstream genes, which results in a myriad of direct (on cancer cells) and indirect (through immune effector cells and vasculature) effects on the tumour. New insights into endogenous and exogenous activation of type I interferons in the tumour and its microenvironment have given impetus to drug discovery and patient evaluation of interferon-directed strategies...
January 24, 2019: Nature Reviews. Drug Discovery
https://read.qxmd.com/read/30679805/the-virtuous-cycle-of-human-genetics-and-mouse-models-in-drug-discovery
#5
REVIEW
Joseph H Nadeau, Johan Auwerx
Ongoing studies in many species seek to understand the origins, architecture and consequences of phenotypic variation under normal and dysfunctional conditions, with the aim of identifying targets for intervention that can prevent, stabilize or reverse disease. Some suggest that only humans are appropriate for studying these questions and argue that candidate drug targets identified in mouse models are largely unreliable. Here, we review the vast evidence showing that mouse models continue to make fundamental contributions to our understanding of genetic principles, pathogenic mechanisms and therapeutic modalities...
January 24, 2019: Nature Reviews. Drug Discovery
https://read.qxmd.com/read/30622344/delivery-technologies-for-cancer-immunotherapy
#6
REVIEW
Rachel S Riley, Carl H June, Robert Langer, Michael J Mitchell
Immunotherapy has become a powerful clinical strategy for treating cancer. The number of immunotherapy drug approvals has been increasing, with numerous treatments in clinical and preclinical development. However, a key challenge in the broad implementation of immunotherapies for cancer remains the controlled modulation of the immune system, as these therapeutics have serious adverse effects including autoimmunity and nonspecific inflammation. Understanding how to increase the response rates to various classes of immunotherapy is key to improving efficacy and controlling these adverse effects...
January 8, 2019: Nature Reviews. Drug Discovery
https://read.qxmd.com/read/30610226/approaches-to-treat-immune-hot-altered-and-cold-tumours-with-combination-immunotherapies
#7
REVIEW
Jérôme Galon, Daniela Bruni
Immunotherapies are the most rapidly growing drug class and have a major impact in oncology and on human health. It is increasingly clear that the effectiveness of immunomodulatory strategies depends on the presence of a baseline immune response and on unleashing of pre-existing immunity. Therefore, a general consensus emerged on the central part played by effector T cells in the antitumour responses. Recent technological, analytical and mechanistic advances in immunology have enabled the identification of patients who are more likely to respond to immunotherapy...
January 4, 2019: Nature Reviews. Drug Discovery
https://read.qxmd.com/read/30610225/therapeutic-targeting-of-the-nrf2-and-keap1-partnership-in-chronic-diseases
#8
REVIEW
Antonio Cuadrado, Ana I Rojo, Geoffrey Wells, John D Hayes, Sharon P Cousin, William L Rumsey, Otis C Attucks, Stephen Franklin, Anna-Liisa Levonen, Thomas W Kensler, Albena T Dinkova-Kostova
The transcription factor NF-E2 p45-related factor 2 (NRF2; encoded by NFE2L2) and its principal negative regulator, the E3 ligase adaptor Kelch-like ECH-associated protein 1 (KEAP1), are critical in the maintenance of redox, metabolic and protein homeostasis, as well as the regulation of inflammation. Thus, NRF2 activation provides cytoprotection against numerous pathologies including chronic diseases of the lung and liver; autoimmune, neurodegenerative and metabolic disorders; and cancer initiation. One NRF2 activator has received clinical approval and several electrophilic modifiers of the cysteine-based sensor KEAP1 and inhibitors of its interaction with NRF2 are now in clinical development...
January 4, 2019: Nature Reviews. Drug Discovery
https://read.qxmd.com/read/30542076/polymer-drug-conjugate-therapeutics-advances-insights-and-prospects
#9
REVIEW
Iriny Ekladious, Yolonda L Colson, Mark W Grinstaff
Polymer-drug conjugates have long been a mainstay of the drug delivery field, with several conjugates successfully translated into clinical practice. The conjugation of therapeutic agents to polymeric carriers, such as polyethylene glycol, offers several advantages, including improved drug solubilization, prolonged circulation, reduced immunogenicity, controlled release and enhanced safety. In this Review, we discuss the rational design, physicochemical characteristics and recent advances in the development of different classes of polymer-drug conjugates, including polymer-protein and polymer-small-molecule drug conjugates, dendrimers, polymer nanoparticles and multifunctional systems...
December 12, 2018: Nature Reviews. Drug Discovery
https://read.qxmd.com/read/30514970/therapeutic-strategies-for-sickle-cell-disease-towards-a-multi-agent-approach
#10
REVIEW
Marilyn J Telen, Punam Malik, Gregory M Vercellotti
For over 100 years, clinicians and scientists have been unravelling the consequences of the A to T substitution in the β-globin gene that produces haemoglobin S, which leads to the systemic manifestations of sickle cell disease (SCD), including vaso-occlusion, anaemia, haemolysis, organ injury and pain. However, despite growing understanding of the mechanisms of haemoglobin S polymerization and its effects on red blood cells, only two therapies for SCD - hydroxyurea and L-glutamine - are approved by the US Food and Drug Administration...
December 4, 2018: Nature Reviews. Drug Discovery
https://read.qxmd.com/read/30504792/therapeutic-potential-of-ectopic-olfactory-and-taste-receptors
#11
REVIEW
Sung-Joon Lee, Inge Depoortere, Hanns Hatt
Olfactory and taste receptors are expressed primarily in the nasal olfactory epithelium and gustatory taste bud cells, where they transmit real-time sensory signals to the brain. However, they are also expressed in multiple extra-nasal and extra-oral tissues, being implicated in diverse biological processes including sperm chemotaxis, muscle regeneration, bronchoconstriction and bronchodilatation, inflammation, appetite regulation and energy metabolism. Elucidation of the physiological roles of these ectopic receptors is revealing potential therapeutic and diagnostic applications in conditions including wounds, hair loss, asthma, obesity and cancers...
November 30, 2018: Nature Reviews. Drug Discovery
https://read.qxmd.com/read/30498203/regulatory-watch-european-regulatory-experience-with-advanced-therapy-medicinal-products
#12
Lisbeth Barkholt, Caroline Voltz-Girolt, June Raine, Tomas Salmonson, Martina Schüssler-Lenz
No abstract text is available yet for this article.
November 30, 2018: Nature Reviews. Drug Discovery
https://read.qxmd.com/read/30498202/non-invasive-delivery-strategies-for-biologics
#13
REVIEW
Aaron C Anselmo, Yatin Gokarn, Samir Mitragotri
Biologics now constitute a significant element of available medical treatments. Owing to their clinical and commercial success, biologics are a rapidly growing class and have become a dominant therapeutic modality. Although most of the successful biologics to date are drugs that bear a peptidic backbone, ranging from small peptides to monoclonal antibodies (~500 residues; 150 kDa), new biologic modalities, such as nucleotide-based therapeutics and viral gene therapies, are rapidly maturing towards widespread clinical use...
November 30, 2018: Nature Reviews. Drug Discovery
https://read.qxmd.com/read/30470818/turning-foes-to-friends-targeting-cancer-associated-fibroblasts
#14
REVIEW
Xueman Chen, Erwei Song
Current paradigms of cancer-centric therapeutics are usually not sufficient to eradicate the malignancy, as the cancer stroma may prompt tumour relapse and therapeutic resistance. Among all the stromal cells that populate the tumour microenvironment, cancer-associated fibroblasts (CAFs) are the most abundant and are critically involved in cancer progression. CAFs regulate the biology of tumour cells and other stromal cells via cell-cell contact, releasing numerous regulatory factors and synthesizing and remodelling the extracellular matrix, and thus these cells affect cancer initiation and development...
November 23, 2018: Nature Reviews. Drug Discovery
https://read.qxmd.com/read/30710142/2018-fda-drug-approvals
#15
Asher Mullard
No abstract text is available yet for this article.
February 2019: Nature Reviews. Drug Discovery
https://read.qxmd.com/read/30710141/2018-fda-approvals-hit-all-time-high-but-average-value-slips-again
#16
Mathias Baedeker, Michael Ringel, Ulrik Schulze
No abstract text is available yet for this article.
February 2019: Nature Reviews. Drug Discovery
https://read.qxmd.com/read/30710140/biopharma-dealmaking-in-2018
#17
Amanda Micklus, Steven Muntner
No abstract text is available yet for this article.
February 2019: Nature Reviews. Drug Discovery
https://read.qxmd.com/read/30710139/developing-closed-loop-neuromodulatory-devices
#18
Sarah Crunkhorn
No abstract text is available yet for this article.
February 2019: Nature Reviews. Drug Discovery
https://read.qxmd.com/read/30710138/role-of-the-protein-data-bank
#19
Sarah Crunkhorn
No abstract text is available yet for this article.
February 2019: Nature Reviews. Drug Discovery
https://read.qxmd.com/read/30710137/top-product-forecasts-for-2019
#20
Lisa Urquhart
No abstract text is available yet for this article.
February 2019: Nature Reviews. Drug Discovery
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