Recent advances in multitarget-directed ligands targeting G-protein-coupled receptors.
Abstract Mounting evidence indicates that single-target drugs might be inadequate to achieve satisfactory therapeutic effects on complex diseases. Recently, increasing attention has been paid to developing drugs that can manipulate multiple targets to generate beneficial effects through potential synergy. G-protein-coupled receptors (GPCRs) become desirable targets for developing multitarget-directed ligands (MTDLs) because of their crucial roles in the pathophysiology of various human diseases and the accessibility of druggable sites at the cell surface. Herein, we review the most recent advances in the developme...
Source: Drug Discovery Today - July 9, 2020 Category: Drugs & Pharmacology Authors: Ma H, Huang B, Zhang Y Tags: Drug Discov Today Source Type: research

Bayer's in silico ADMET platform: a journey of machine learning over the past two decades.
h A Abstract Over the past two decades, an in silico absorption, distribution, metabolism, and excretion (ADMET) platform has been created at Bayer Pharma with the goal to generate models for a variety of pharmacokinetic and physicochemical endpoints in early drug discovery. These tools are accessible to all scientists within the company and can be a useful tool in assisting with the selection and design of novel leads, as well as the process of lead optimization. Here. we discuss the development of machine-learning (ML) approaches with special emphasis on data, descriptors, and algorithms. We show that high compa...
Source: Drug Discovery Today - July 8, 2020 Category: Drugs & Pharmacology Authors: Göller AH, Kuhnke L, Montanari F, Bonin A, Schneckener S, Ter Laak A, Wichard J, Lobell M, Hillisch A Tags: Drug Discov Today Source Type: research

Advanced glycation end products in diabetes, cancer and phytochemical therapy.
Abstract The irreversible glycation and oxidation of proteins and lipids produces advanced glycation end products (AGEs). These modified AGEs are triggered to bind the receptor for AGE (RAGE), thereby activating its downstream signaling pathways, such as nuclear factor (NF)-κB and phosphoinositide 3-kinase (PI3K)/Akt, ultimately leading to diabetes and cancers. In this review, we focus on the interaction of AGE-RAGE and their associated pathways. We also consider the activity of phytochemicals, such as genistein and curcumin, that trap dicarbonyl compounds including methylglyoxal (MG) and glyoxalase that ari...
Source: Drug Discovery Today - July 8, 2020 Category: Drugs & Pharmacology Authors: Dariya B, Nagaraju GP Tags: Drug Discov Today Source Type: research

Exploring CYP2J2: lipid mediators, inhibitors and therapeutic implications.
Abstract In contrast to other drug-metabolizing cytochrome P450 (CYP) oxygenases, CYP2J2 shows considerable extrahepatic activity and is responsible for the olefin epoxidation of several polyunsaturated fatty acid (PUFA) precursors. The resulting epoxylipids act as signaling mediators and show a remarkable variety of biological functions. Recent studies suggest a role of selected CYP2J2-derived epoxylipids and their metabolites in chronic pain, as well as angiogenesis, hematopoiesis, metabolic disorders, and tumor growth. These pleiotropic effects of CYP products imply that targeting CYP2J2 could represent a novel...
Source: Drug Discovery Today - July 8, 2020 Category: Drugs & Pharmacology Authors: Sisignano M, Steinhilber D, Parnham MJ, Geisslinger G Tags: Drug Discov Today Source Type: research

Repositioning chloroquine as antiviral prophylaxis against COVID-19: potential and challenges.
Abstract The Coronavirus Disease 2019 (COVID-19) pandemic is advancing globally, and pharmaceutical prophylaxis is one solution. Here, we propose repositioning chloroquine (CQ) as prophylaxis against COVID-19. CQ blocks viral attachment and entry to host cells and demonstrates efficacy against a variety of viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. Furthermore, CQ is safe, inexpensive, and available. Here, we review the antiviral mechanisms of CQ, its in vitro activity against coronaviruses, its pharmacokinetics (PK) and adverse effects, and wh...
Source: Drug Discovery Today - July 3, 2020 Category: Drugs & Pharmacology Authors: Chang R, Sun WZ Tags: Drug Discov Today Source Type: research

Polymer-drug conjugates: recent advances and future perspectives.
Abstract Polymer-drug conjugates (PDC) have exhibited clinical and commercial success in the field of drug delivery. A polymeric backbone, linker, targeting moiety, and drug constitute the building blocks of PDCs. Current attention is focusing on natural polymeric carriers, in particular the concept of graft copolymers, such as a combination of polymers and polysaccharides, to explore dual benefits such as combined vehicles and targeting moieties. Polymer heterogeneity, synthesis of PDCs, broad molecular weight distribution, conjugate variability, immunogenicity of polymers, safety, stability, and stringent regula...
Source: Drug Discovery Today - July 3, 2020 Category: Drugs & Pharmacology Authors: Thakor P, Bhavana V, Sharm R, Srivastava S, Singh SB, Mehra NK Tags: Drug Discov Today Source Type: research

Engineering extracellular matrix to improve drug delivery for cancer therapy.
Abstract As an effective platform to deliver therapeutic drugs into tumors, nanoparticles (NPs) have shown great potential for cancer therapy. However, the tumor microenvironment (TME) contains diverse barriers to the transport of NPs, particularly the dense extracellular matrix (ECM). Thus, engineering the tumor ECM is a promising way to improve drug delivery by degrading existing ECM and/or blocking ECM synthesis. In this review, we present the state-of-the-art advances in engineering the tumor ECM to improve the therapeutic efficacy of NPs, and highlight their advantages and limitations. PMID: 32629171 [Pu...
Source: Drug Discovery Today - July 3, 2020 Category: Drugs & Pharmacology Authors: He X, Yang Y, Li L, Zhang P, Guo H, Liu N, Yang X, Xu F Tags: Drug Discov Today Source Type: research

Modulating the modulators: regulation of protein arginine methyltransferases by post-translational modifications.
Abstract The therapeutic potential of targeting protein arginine methyltransferases (PRMTs) is inextricably linked to their key roles in various cellular functions, including splicing, proliferation, cell cycle regulation, differentiation, and DNA damage signaling. Unsurprisingly, the development of inhibitors against these enzymes has become a rapidly expanding research area. However, effective targeting of PRMTs requires a deeper understanding of the mechanistic details behind their regulation at multiple levels, involving those mechanisms that alter their activity, interactions, and localization. Recently, post...
Source: Drug Discovery Today - July 3, 2020 Category: Drugs & Pharmacology Authors: Hartley AV, Lu T Tags: Drug Discov Today Source Type: research

Nanovehicles for co-delivery of anticancer agents.
Abstract Effective cancer treatment remains a significant challenge in human healthcare. Although many different types of cancer therapy have been tested, scientists have now concluded that combinations of drugs, or drugs plus gene therapy, can target multiple pathways to fight cancer. Nanovehicles can increase drug uptake inside tumor cells, improve biodistribution and accumulation at tumor sites. The ability to deliver two or more anticancer drugs, genes, among others, at the same time and place will increase therapeutic effects while decreasing side effects and reducing the risk of multidrug resistance. This re...
Source: Drug Discovery Today - July 2, 2020 Category: Drugs & Pharmacology Authors: Zeinali M, Abbaspour-Ravasjani S, Ghorbani M, Babazadeh A, Soltanfam T, Santos AC, Hamishehkar H, Hamblin MR Tags: Drug Discov Today Source Type: research

Treatments of trimethylaminuria: where we are and where we might be heading.
Abstract Trimethylamine (TMA) is a volatile, foul-smelling, diet-derived amine, primarily generated in the colon and metabolized in the liver to its odorless N-oxide (TMAO). In primary trimethylaminuria (TMAU), an inherited deficiency in flavin-containing monooxygenase 3 leads to elevated systemic TMA levels. The excretion of elevated amounts of TMA in sweat, breath, urine and other bodily secretions gives individuals affected by TMAU a smell resembling that of rotten fish. Although the disorder might not seem an important health problem, its social and psychological burden can be devastating. To date, no treatmen...
Source: Drug Discovery Today - June 29, 2020 Category: Drugs & Pharmacology Authors: Schmidt AC, Leroux JC Tags: Drug Discov Today Source Type: research

A pragmatic tool for drug discovery.
PMID: 32593660 [PubMed - as supplied by publisher] (Source: Drug Discovery Today)
Source: Drug Discovery Today - June 25, 2020 Category: Drugs & Pharmacology Authors: Bobbitt DR, Merson L, Reith C, Bao W, Okada M, Facile R Tags: Drug Discov Today Source Type: research

3 tips for pharma startup success.
PMID: 32593661 [PubMed - as supplied by publisher] (Source: Drug Discovery Today)
Source: Drug Discovery Today - June 25, 2020 Category: Drugs & Pharmacology Authors: Cunningham S Tags: Drug Discov Today Source Type: research

Prevention of COVID-19 by drug repurposing: rationale from drugs prescribed for mental disorders.
PMID: 32593662 [PubMed - as supplied by publisher] (Source: Drug Discovery Today)
Source: Drug Discovery Today - June 25, 2020 Category: Drugs & Pharmacology Authors: Villoutreix BO, Beaune PH, Tamouza R, Krishnamoorthy R, Leboyer M Tags: Drug Discov Today Source Type: research

Patent lifecycle management strategies in open innovation projects.
This article investigates the ownership of follow-on patents for approved drugs in the USA. We discover that a considerable number of follow-on patents are originally developed by, and issued to, external partners and not drug sponsors. We also find that the use of follow-on patents is more common in some therapeutic areas than in others. Based on these findings, we develop lifecycle strategies to effectively manage and use external patents in open innovation projects. These strategies include proper license contract design, post-FDA-approval acquisition and open innovation. PMID: 32592662 [PubMed - as supplied by pub...
Source: Drug Discovery Today - June 24, 2020 Category: Drugs & Pharmacology Authors: Lee Y, Fong EA Tags: Drug Discov Today Source Type: research

Emerging vaccine delivery systems for COVID-19: Functionalised silica nanoparticles offer a potentially safe and effective alternative delivery system for DNA/RNA vaccines and may be useful in the hunt for a COVID-19 vaccine.
PMID: 32592866 [PubMed - as supplied by publisher] (Source: Drug Discovery Today)
Source: Drug Discovery Today - June 24, 2020 Category: Drugs & Pharmacology Authors: Theobald N Tags: Drug Discov Today Source Type: research

The rise of molecular simulations in fragment-based drug design (FBDD): an overview.
Abstract Fragment-based drug discovery (FBDD) is an innovative approach, progressively more applied in the academic and industrial context, to enhance hit identification for previously considered undruggable biological targets. In particular, FBDD discovers low-molecular-weight (LMW) ligands (
Source: Drug Discovery Today - June 24, 2020 Category: Drugs & Pharmacology Authors: Bissaro M, Sturlese M, Moro S Tags: Drug Discov Today Source Type: research

Direct SARS-CoV-2 infection of the heart potentiates the cardiovascular sequelae of COVID-19.
PMID: 32592868 [PubMed - as supplied by publisher] (Source: Drug Discovery Today)
Source: Drug Discovery Today - June 24, 2020 Category: Drugs & Pharmacology Authors: Bose RJ, McCarthy JR Tags: Drug Discov Today Source Type: research

Current and future therapeutical approaches for COVID-19.
Abstract We review the evolution of our clinical understanding of COVID-19, possible therapeutic targets, and prospects for COVID-19 management. PMID: 32574697 [PubMed - as supplied by publisher] (Source: Drug Discovery Today)
Source: Drug Discovery Today - June 20, 2020 Category: Drugs & Pharmacology Authors: Duan Y, Yao Y, Kumar SA, Zhu HL, Chang J Tags: Drug Discov Today Source Type: research

Treating age-related multimorbidity: the drug discovery challenge.
Abstract Patients with multimorbidities have shorter life expectancy and their clinical management is more complex and expensive for healthcare systems currently focused on treating single diseases. Given that age is the major risk factor for multimorbidity, the challenge of treating these patients will only increase in coming years. Here, we review the case for targeting the core processes that drive the ageing phenotype as a novel pharmaceutical approach to multimorbidity. There is growing evidence that targeting ageing mechanisms can reduce or delay age-related diseases in animal models, and the first reports o...
Source: Drug Discovery Today - June 20, 2020 Category: Drugs & Pharmacology Authors: Ermogenous C, Green C, Jackson T, Ferguson M, Lord JM Tags: Drug Discov Today Source Type: research

Discovering small-molecule therapeutics against SARS-CoV-2.
Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become a global health pandemic. The lack of effective treatments, coupled with its etiology, has resulted in more than 400,000 deaths at the time of writing. The SARS-CoV-2 genome is highly homologous to that of SARS-CoV, the causative agent behind the 2003 SARS outbreak. Based on prior reports, clinicians have pursued the off-label use of several antiviral drugs, while the scientific community has responded by seeking agents against traditional targets, especially viral proteases. However, several avenues remain unexplored, includi...
Source: Drug Discovery Today - June 20, 2020 Category: Drugs & Pharmacology Authors: Tiwari V, Beer JC, Sankaranarayanan NV, Swanson-Mungerson M, Desai UR Tags: Drug Discov Today Source Type: research

Exportin 1 inhibition as antiviral therapy.
Abstract Coronavirus 2019 (COVID-19; caused by Severe Acute Respiratory Syndrome Coronavirus 2; SARS-CoV-2) is a currently global health problem. Previous studies showed that blocking nucleocytoplasmic transport with exportin 1 (XPO1) inhibitors originally developed as anticancer drugs can quarantine key viral accessory proteins and genomic materials in the nucleus of host cell and reduce virus replication and immunopathogenicity. These observations support the concept of the inhibition of nuclear export as an effective strategy against an array of viruses, including influenza A, B, and SARS-CoV. Clinical studies ...
Source: Drug Discovery Today - June 19, 2020 Category: Drugs & Pharmacology Authors: Uddin MH, Zonder JA, Azmi AS Tags: Drug Discov Today Source Type: research

Degraders early developability assessment: face-to-face with molecular properties.
Abstract Pharmaceutical scientists have huge expectations from heterobifunctional small molecule degraders to treat diseases with an unmet medical need. However, degraders are large and flexible and pose significant challenges in terms of cellular uptake and bioavailability. An efficient property-based design is therefore required to discover new oral degrader medicines. Here, we show the non-transferability to degraders with in silico tools routinely implemented in small molecule drug discovery programs; and provide ionization, lipophilicity, polarity and chameleonicity data for a series of seven degraders. We al...
Source: Drug Discovery Today - June 18, 2020 Category: Drugs & Pharmacology Authors: Ermondi G, Vallaro M, Caron G Tags: Drug Discov Today Source Type: research

Human microbial metabolite mimicry as a strategy to expand the chemical space of potential drugs.
ml;ller R Abstract The concept of small-molecule mimicry even of weak microbial metabolites present in rodents and humans, as a means to expand drug repertoires, is new. Hitherto, there are few proof-of-concept papers demonstrating utility of this concept. More recently, papers demonstrating mimicry of intestinal microbial metabolites could expand the drug repertoire for diseases such as inflammatory bowel disease (IBD). We opine that, as more functional metabolite-receptor pairings are discovered, small-molecule metabolite mimicry could be a significant effort in drug discovery. PMID: 32562605 [PubMed - as s...
Source: Drug Discovery Today - June 17, 2020 Category: Drugs & Pharmacology Authors: Li H, Ranhotra HS, Mani S, Dvořák Z, Sokol H, Müller R Tags: Drug Discov Today Source Type: research

Breakthrough therapy-designated oncology drugs: are they rightfully criticized?
Abstract The US Food and Drug Administration (FDA) has four expedited programs, including the breakthrough therapy designation (BTD). Recently, this program has been criticized. In this feature, we determine whether BTD oncology drugs were truly a breakthrough, based on the outcome of a validated instrument to measure clinical benefit. We find that only a few drugs were likely a breakthrough, indicating that the success rate of the BTD program is somewhat low. Despite this, we believe that programs for fast drug approval do have a place in the current regulatory practice and that the necessary efforts for their im...
Source: Drug Discovery Today - June 17, 2020 Category: Drugs & Pharmacology Authors: Mulder J, Pasmooij AMG, Stoyanova-Beninska VV, Schellens JHM Tags: Drug Discov Today Source Type: research

pH-dependent ileocolonic drug delivery, part II: preclinical evaluation of novel drugs and novel excipients.
Abstract Safety issues require that novel drugs and novel excipients, formulated in pH-dependent ileocolonic drug delivery systems, are tested in appropriate animal species before they are evaluated in humans. In a literature search, we found that, of the most frequently used laboratory animal species, the rabbit is the best choice. Its gastrointestinal (GI) pH values most resembles those in humans. In cases where rabbits cannot be used, pigs, dogs, and rats can serve as an alternative provided that GI pH values of individual animals are checked. Various methods to investigate the performance of ileocolonic drug d...
Source: Drug Discovery Today - June 17, 2020 Category: Drugs & Pharmacology Authors: Broesder A, Kosta AMAC, Woerdenbag HJ, Nguyen DN, Frijlink HW, Hinrichs WLJ Tags: Drug Discov Today Source Type: research

COVID-19 and pneumonia: a role for the uPA/uPAR system.
Abstract Here, we highlight recent findings on the urokinase plasminogen activator (uPA)/uPA receptor (uPAR) system that suggest its potential role as a main orchestrator of fatal progression to pulmonary, kidney, and heart failure in patients with coronavirus. Patients with prolonged background inflammation can present with aberrant inflammatory reactions, well recognized as the main factors that can result in death and probably sustained by a dysregulated uPA/uPAR system. SuPAR, the soluble form of uPAR, represents a biomarker of disease progression, and its levels correlate well with comorbidities associated wi...
Source: Drug Discovery Today - June 17, 2020 Category: Drugs & Pharmacology Authors: D'Alonzo D, De Fenza M, Pavone V Tags: Drug Discov Today Source Type: research

PDE5 and PDE10 inhibition activates cGMP/PKG signaling to block Wnt/ β-catenin transcription, cancer cell growth, and tumor immunity.
PDE5 and PDE10 inhibition activates cGMP/PKG signaling to block Wnt/β-catenin transcription, cancer cell growth, and tumor immunity. Drug Discov Today. 2020 Jun 17;: Authors: Piazza GA, Ward A, Chen X, Maxuitenko Y, Coley A, Aboelella NS, Buchsbaum DJ, Boyd MR, Keeton AB, Zhou G Abstract Although numerous reports conclude that nonsteroidal anti-inflammatory drugs (NSAIDs) have anticancer activity, this common drug class is not recommended for long-term use because of potentially fatal toxicities from cyclooxygenase (COX) inhibition. Studies suggest the mechanism responsible for the anticancer act...
Source: Drug Discovery Today - June 17, 2020 Category: Drugs & Pharmacology Authors: Piazza GA, Ward A, Chen X, Maxuitenko Y, Coley A, Aboelella NS, Buchsbaum DJ, Boyd MR, Keeton AB, Zhou G Tags: Drug Discov Today Source Type: research

Applications of magnetotactic bacteria and the magnetosome for cancer treatment.
;ry E Abstract Magnetotactic bacteria (MTB) synthesize iron oxide (Fe3O4) nanoparticles (NPs), called magnetosomes, with large sizes leading to ferrimagnetic behavior and a stable magnetic moment at physiological temperature, a chain structure that prevents NP aggregation and promotes a uniform NP distribution, and a mineral core of magnetite/maghemite composition, which can be stabilized by an organic coating. Such properties can favor magnetosome administration to humans under certain optimized nontoxic conditions of fabrication. In this review, I describe the fabrication methods, physicochemical properties, and...
Source: Drug Discovery Today - June 16, 2020 Category: Drugs & Pharmacology Authors: Alphandéry E Tags: Drug Discov Today Source Type: research

Image-based high-content screening in drug discovery.
Abstract While target-based drug discovery strategies rely on the precise knowledge of the identity and function of the drug targets, phenotypic drug discovery (PDD) approaches allow the identification of novel drugs based on knowledge of a distinct phenotype. Image-based high-content screening (HCS) is a potent PDD strategy that characterizes small-molecule effects through the quantification of features that depict cellular changes among or within cell populations, thereby generating valuable data sets for subsequent data analysis. However, these data can be complex, making image analysis from large HCS campaigns...
Source: Drug Discovery Today - June 16, 2020 Category: Drugs & Pharmacology Authors: Lin S, Schorpp K, Rothenaigner I, Hadian K Tags: Drug Discov Today Source Type: research

Application of mesoporous silica nanoparticles as drug delivery carriers for chemotherapeutic agents.
Abstract Recently, remarkable efforts have focused on research towards enhancing and delivering efficacious and advanced therapeutic agents. Even though this involves significant challenges, innovative techniques and materials have been explored to overcome these. The advantageous properties of mesoporous silica nanoparticles (MSNs), such as unique morphologies and geometries, makes then favorable for use for various drug delivery targeting purposes, particularly in cancer therapy. As we discuss here, MSNs have been utilized over the past few decades to improve the efficiency of anticancer drugs by enhancing their...
Source: Drug Discovery Today - June 16, 2020 Category: Drugs & Pharmacology Authors: Alyassin Y, Sayed EG, Mehta P, Ruparelia K, Arshad MS, Rasekh M, Shepherd J, Kucuk I, Wilson PB, Singh N, Chang MW, Fatouros DG, Ahmad Z Tags: Drug Discov Today Source Type: research

pH-dependent ileocolonic drug delivery, part I: in vitro and clinical evaluation of novel systems.
Abstract pH-dependent ileocolonic drug delivery systems rely on the sharp pH peak reaching 7.2-7.7 usually found in the ileum of healthy individuals and patients with colonic diseases. The pH dependency of novel drug delivery systems should first be evaluated in in vitro dissolution tests mimicking the human gastrointestinal (GI) pH profile and buffer composition. When proven successful in vitro, the clinical applicability of a novel system should be confirmed in humans. Various methods have been published to verify ileocolonic drug delivery in humans. Of those, we recommend the caffeine-sulfasalazine method and t...
Source: Drug Discovery Today - June 15, 2020 Category: Drugs & Pharmacology Authors: Broesder A, Woerdenbag HJ, Prins GGH, Nguyen DN, Frijlink HW, Hinrichs WLJ Tags: Drug Discov Today Source Type: research

Phytonanomedicine: a novel avenue to treat recurrent cancer by targeting cancer stem cells.
Abstract Research suggests that tumor relapse and metastasis is caused by minor population of tumor-initiating cells called cancer stem cells (CSCs), which exhibit self-renewability, quiescence, antiapoptosis, and drug resistance. Conventional chemotherapeutics target rapidly proliferating cells but fail to exert cytotoxic effects on CSCs, thus enriching them and driving metastasis and relapse. Hence, targeting CSCs is essential for developing novel therapies for effective cancer treatment. Pertaining to this, several phytochemicals have been identified that exhibit anti-CSC activity. However, poor pharmacokinetic...
Source: Drug Discovery Today - June 15, 2020 Category: Drugs & Pharmacology Authors: Mohapatra P, Singh P, Sahoo SK Tags: Drug Discov Today Source Type: research

Oseltamivir analogs with potent anti-influenza virus activity.
Abstract Influenza A and B viruses cause seasonal worldwide influenza epidemics each winter, and are a major public health concern and cause of morbidity and mortality. A substantial reduction in influenza-related deaths can be attributed to both vaccination and administration of oseltamivir (OS), which is approved for oral administration and inhibits viral neuraminidase (NA), a transmembrane protein. OS carboxylate (OSC), the active form of OS, is formed by the action of endogenous esterase, which targets NA and is shown to significantly reduce influenza-related deaths. However, the development of resistance in v...
Source: Drug Discovery Today - June 15, 2020 Category: Drugs & Pharmacology Authors: Kumar S, Goicoechea S, Kumar S, Pearce CM, Durvasula R, Kempaiah P, Rathi B, Poonam Tags: Drug Discov Today Source Type: research

The upside of being a digital pharma player.
Abstract We investigated the state of artificial intelligence (AI) in pharmaceutical research and development (R&D) and outline here a risk and reward perspective regarding digital R&D. Given the novelty of the research area, a combined qualitative and quantitative research method was chosen, including the analysis of annual company reports, investor relations information, patent applications, and scientific publications of 21 pharmaceutical companies for the years 2014 to 2019. As a result, we can confirm that the industry is in an 'early mature' phase of using AI in R&D. Furthermore, we can demonstra...
Source: Drug Discovery Today - June 15, 2020 Category: Drugs & Pharmacology Authors: Schuhmacher A, Gatto A, Hinder M, Kuss M, Gassmann O Tags: Drug Discov Today Source Type: research

Targeting post-translational modification of transcription factors as cancer therapy.
Abstract Dysregulated transcription factors (TFs) fuel aberrant gene expression networks, resulting in cell overproliferation, migration, and immunosuppression. Given that TFs are regarded to have vital roles in tumors, various approaches are exploited to modulate their activities. Nevertheless, except for some ligand-binding nuclear receptors, most TFs are still considered 'undruggable' targets. Responding to extra- or intracellular stimuli, TFs are decorated with an array of post-translational modifications (PTMs) to regulate their subcellular localizations, protein-protein/DNA interactions, and stability. These...
Source: Drug Discovery Today - June 12, 2020 Category: Drugs & Pharmacology Authors: Qian M, Yan F, Yuan T, Yang B, He Q, Zhu H Tags: Drug Discov Today Source Type: research

Prussian blue nanoparticles: synthesis, surface modification, and biomedical applications.
Abstract Prussian blue nanoparticles (PBNPs) are a nanomaterial that presents unique properties and an excellent biocompatibility. They can be synthesized in mild conditions and can be derivatized with polymers and/or biomolecules. PBNPs are used in biomedicine as therapy and diagnostic agents. In biomedical imaging, PBNPs constitute contrast agents in photoacoustic and magnetic resonance imaging (MRI). They are a good adsorbent to be used as antidotes for poisoning with cesium and/or thallium ions. Moreover, the ability to convert energy into heat makes them useful photothermal agents (PAs) in photothermal therap...
Source: Drug Discovery Today - May 31, 2020 Category: Drugs & Pharmacology Authors: Busquets MA, Estelrich J Tags: Drug Discov Today Source Type: research

Old active ingredients in new medicinal products: is the regulatory path coherent with patients' expectations?
Abstract The rising costs of new medicinal products are a challenge to the economic sustainability of national healthcare systems in ensuring patients' access to therapies. European Union (EU) and US legislators have provided regulatory pathways aimed at simplifying Marketing Authorization (MA) applications for new medicinal products in cases when safety and efficacy profiles can be derived from the data of already-marketed products. In this review, we discuss the different regulatory pathways towards the MA of new medicinal products containing old drug substances and intended to improve the therapeutic value of a...
Source: Drug Discovery Today - May 30, 2020 Category: Drugs & Pharmacology Authors: Minghetti P, Musazzi UM, Casiraghi A, Rocco P Tags: Drug Discov Today Source Type: research

Antibody-drug conjugates targeting RON receptor tyrosine kinase as a novel strategy for treatment of triple-negative breast cancer.
Abstract Treatment of triple-negative breast cancer (TNBC) is a challenge to oncologists. Currently, the lack of effective therapy has fostered a major effort to discover new targets and therapeutics to combat this disease. The recepteur d'origine nantais (RON) receptor has been implicated in the pathogenesis of TNBC. Clinical studies have revealed that aberrant RON expression is crucial in regulating TNBC malignant phenotypes. Increased RON expression also has prognostic value for breast cancer progress. These features provide the rationale to target RON for TNBC treatment. In this review, we discuss the importan...
Source: Drug Discovery Today - May 29, 2020 Category: Drugs & Pharmacology Authors: Yao HP, Suthe SR, Hudson R, Wang MH Tags: Drug Discov Today Source Type: research

Prophylactic aspirin for preventing pre-eclampsia and its complications: An overview of meta-analyses.
Abstract Pre-eclampsia is a significant risk factor for adverse outcomes for both the fetus and mother. Research has suggested that antiplatelet drugs, such as aspirin, could prevent pre-eclampsia, although meta-analyses have reported inconsistent outcomes. Therefore, we analyzed 12 such meta-analyses to provide a comprehensive overview of the effects of aspirin during pregnancy. Aspirin was associated with a significant reduction in pre-eclampsia, preterm labor, and intrauterine growth restriction (IUGR) if started at or before 16 weeks of gestational age. After 16 weeks, aspirin significantly reduced the inciden...
Source: Drug Discovery Today - May 29, 2020 Category: Drugs & Pharmacology Authors: Ghazanfarpour M, Sathyapalan T, Banach M, Jamialahmadi T, Sahebkar A Tags: Drug Discov Today Source Type: research

Genetic profile considerations for induction of allogeneic chimerism as a therapeutic approach for type 1 diabetes mellitus.
Abstract The major therapeutic modality for type 1 diabetes mellitus (T1DM) remains sustaining euglycemia by exogenous administration of insulin. Based on a new understanding of bone marrow structural and functional dynamics, a conditioning-free bone marrow transplantation (BMT), with reduced adverse effects, opens the possibility for evaluating β cell regeneration and restoration of euglycemia by induction of allogeneic chimerism in patients T1DM, as shown in a mouse model. With this therapeutic modality, donor bone marrow (BM) selection based on T1DM-predisposing and preventive phenotypes will improve treat...
Source: Drug Discovery Today - May 20, 2020 Category: Drugs & Pharmacology Authors: Black LA, Zorina T Tags: Drug Discov Today Source Type: research

Long noncoding RNAs in nonalcoholic fatty liver disease and liver fibrosis: state-of-the-art and perspectives in diagnosis and treatment.
Abstract Nonalcoholic fatty liver disease (NAFLD) significantly impacts global health. Despite considerable research, its pathophysiology remains partially unclear. In addition, selective serum biomarkers of disease diagnosis and progression are missing. Long noncoding RNAs (lncRNAs) are a heterogeneous group of ncRNAs with crucial roles in biological processes underlying the pathophysiology of different human diseases. Recent studies have shown that lncRNA could be associated with the genesis and progression of NAFLD towards the most severe forms. Although the field is still in its infancy, it is tempting to spec...
Source: Drug Discovery Today - May 19, 2020 Category: Drugs & Pharmacology Authors: De Vincentis A, Rahmani Z, Muley M, Vespasiani-Gentilucci U, Ruggiero S, Zamani P, Jamialahmadi T, Sahebkar A Tags: Drug Discov Today Source Type: research

A systems biology approach for studying neurodegenerative diseases.
Abstract Neurodegenerative diseases (NDDs), such as Alzheimer's (AD) and Parkinson's (PD), are among the leading causes of lost years of healthy life and exert a great strain on public healthcare systems. Despite being first described more than a century ago, no effective cure exists for AD or PD. Although extensively characterised at the molecular level, traditional neurodegeneration research remains marred by narrow-sense approaches surrounding amyloid β (Aβ), tau, and α-synuclein (α-syn). A systems biology approach enables the integration of multi-omics data and informs discovery of biomar...
Source: Drug Discovery Today - May 19, 2020 Category: Drugs & Pharmacology Authors: Lam S, Bayraktar A, Zhang C, Turkez H, Nielsen J, Boren J, Shoaie S, Uhlen M, Mardinoglu A Tags: Drug Discov Today Source Type: research

Long-acting microneedles: a progress report of the state-of-the-art techniques.
Abstract Microneedles (MNs) are a self-administrable and painless alternative to hypodermic needles for bolus drug delivery. Sustained drug release is the preferable drug delivery method because it reduces the chemical burden in patients and can deliver therapeutics that require long-term exposure. Here, we review recent advances in long-acting MNs, summarizing polymers used to fabricate long-acting MNs and mechanisms controlling drug release. We also introduce novel designs of separable needles to achieve implantable tips and bioinspired needles for enhanced skin adhesion, as well as strategies using the back lay...
Source: Drug Discovery Today - May 18, 2020 Category: Drugs & Pharmacology Authors: Chen Z, He J, Qi J, Zhu Q, Wu W, Lu Y Tags: Drug Discov Today Source Type: research

Tight junction modulators for drug delivery to the central nervous system.
Abstract Overcoming the blood-brain barrier (BBB) to enable the treatment of central nervous system (CNS) diseases is an active field of research. Modulating or opening the tight junctions (TJs) in brain endothelial cells is one method to enable a range of small-molecular-weight drugs to cross the BBB via the paracellular route. Over the past 2 decades, the molecular understanding of TJ proteins in the BBB has significantly improved, and several agonists and antagonists have been tested for modulation of the TJs. In this review, we discuss the composition of TJ proteins in the BBB and introduce indirect pharmacolo...
Source: Drug Discovery Today - May 18, 2020 Category: Drugs & Pharmacology Authors: Hashimoto Y, Tachibana K, Kondoh M Tags: Drug Discov Today Source Type: research

CCK2R antagonists: from SAR to clinical trials.
Abstract The widespread involvement of the cholecystokinin-2/gastrin receptor (CCK2R) in multiple (patho)physiological processes has propelled extensive searches for nonpeptide small-molecule CCK2R antagonists. For the past three decades, considerable research has yielded numerous chemically heterogeneous compounds. None of these entered into the clinic, mainly because of inadequate biological effects. However, it appears that the ultimate goal of a clinically useful CCK2R antagonist is now just around the corner, with the most promising compounds, netazepide and nastorazepide, now in Phase II clinical trials. Her...
Source: Drug Discovery Today - May 18, 2020 Category: Drugs & Pharmacology Authors: Novak D, Anderluh M, Peitl PK Tags: Drug Discov Today Source Type: research

Advances in the computational development of androgen receptor antagonists.
Abstract The androgen receptor is a ligand-dependent transcriptional factor and an essential therapeutic target for prostate cancer. Competitive binding of antagonists to the androgen receptor can alleviate aberrant activation of the androgen receptor in prostate cancer. In recent years, computer-aided drug design has played an essential part in the discovery of novel androgen receptor antagonists. This review summarizes the recent advances in the discovery of novel androgen receptor antagonists through computer-aided drug design approaches; and discusses the applications of molecular modeling techniques to unders...
Source: Drug Discovery Today - May 18, 2020 Category: Drugs & Pharmacology Authors: Hu X, Chai X, Wang X, Duan M, Pang J, Fu W, Li D, Hou T Tags: Drug Discov Today Source Type: research

Rodent models of diabetic kidney disease: human translatability and preclinical validity.
nk LN Abstract Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD). Except for SGLT2 inhibitors and GLP-1R agonists, there have been few changes in DKD treatment over the past 25 years, when multifactorial intervention was introduced in patients with type 2 diabetes mellitus (T2DM). The unmet clinical need is partly due to the lack of animal models that replicate clinical features of human DKD, which has raised concern about the utility of these models in preclinical drug discovery. In this review, we performed a comprehensive analysis of rodent models of DKD to compare treatment e...
Source: Drug Discovery Today - May 13, 2020 Category: Drugs & Pharmacology Authors: Sembach FE, Østergaard MV, Vrang N, Feldt-Rasmussen B, Fosgerau K, Jelsing J, Fink LN Tags: Drug Discov Today Source Type: research

Shotgun drug repurposing biotechnology to tackle epidemics and pandemics.
PMID: 32405249 [PubMed - as supplied by publisher] (Source: Drug Discovery Today)
Source: Drug Discovery Today - May 13, 2020 Category: Drugs & Pharmacology Authors: Mangione W, Falls Z, Melendy T, Chopra G, Samudrala R Tags: Drug Discov Today Source Type: research

SCHOOL of nature: ligand-independent immunomodulatory peptides.
Abstract Groundbreaking studies in protein biophysics have identified the mechanisms of transmembrane signaling at the level of druggable protein-protein interactions (PPIs). This resulted in the development of the signaling chain homooligomerization (SCHOOL) strategy to modulate cell responses using receptor-specific peptides. Inspired by nature, these short peptides use ligand-independent mechanisms of receptor inhibition and demonstrate potent efficacy in vitro and in vivo. The SCHOOL strategy is especially important when receptor ligands are unknown. An example is the triggering receptor expressed on myeloid c...
Source: Drug Discovery Today - May 12, 2020 Category: Drugs & Pharmacology Authors: Sigalov AB Tags: Drug Discov Today Source Type: research

Role of oxidative stress in depression.
Abstract Reactive oxygen species (ROS) have vital roles in cellular signaling and in defence against invasive microorganisms. Excessive ROS generation and exhaustion of antioxidative defences trigger proinflammatory signaling, damaging vital macromolecules and inducing cellular apoptosis. The failure of cells to maintain redox homeostasis and resultant generation of proinflammatory mediators leads to cell necrosis. The brain is more vulnerable to oxidative stress (OS) because of its higher oxygen consumption, higher lipid content, and weaker antioxidative defence. OS is a main cause of neurodegeneration and its in...
Source: Drug Discovery Today - May 8, 2020 Category: Drugs & Pharmacology Authors: Bhatt S, Nagappa AN, Patil CR Tags: Drug Discov Today Source Type: research