The latest issue of Drug Discovery Today is packed full of industry focused research articles, new developments in drug discovery, and expert comment and opinion.
• New approvals for cancer have increased dramatically since 1990.
• Biotechnology takes the dominant role in early-stage development, whereas pharmaceutical companies gain in the most approvals. • Kinases in general and tyrosine kinases in particular represent almost half of newly approved cancer drugs.
• Insufficient drug uptake by tumors is the major problem of systemic chemotherapy. • Systemic drug dose increase offered limited benefits and resulted in toxicities. • Loco-regional delivery increased drug doses in tumors with low systemic toxicity. • Although very high doses in tumors achieved, survival benefits are not sufficient. • We review new RRH approach applications in loco-regional cancer treatment.
• We provide an overview about multi-target drug discovery in inflammation. • The molecular pharmacology of prominent anti-inflammatory natural products is presented. • The potential of nature providing privileged structures is discussed. • We describe a multi-target concept inspired by nature. • Major challenges of the multi-target approach for natural products are addressed.
This article fosters a multi-target concept that makes use of the apparent beneficial broad target profile of well-characterized anti-inflammatory natural lead compounds with privileged structures.
•Epigenetic mechanisms are important in the brain development.
•Hypoxia is a common form of intrauterine stress. •Hypoxic-ischemic brain injury is a leading cause of neonatal mortality and subsequent neurological disorders. •Epigenetic mechanisms play a key role in programming of increased risk of ischemic brain injury.
•Pharmacoepidemiology studies need to consider a myriad of approved drugs. •Undetected immunogenicity of biotherapeutics can impact patient safety. •Anti-drug antibodies can decrease or abolish drug efficacy. •A paradigm shift is needed to exploit knowledge gaps during drug approvals. •Patient megadata offer an opportunity to reassess therapeutic drugs.
Analysis of therapeutic drug postmarketing megadata, coupled with regulatory monitoring, can improve patient safety and advancement of science, and decrease healthcare costs.
•The fundamentals of correlation analysis and QSAR modeling have been reported. •Quantum chemical-based QSARs have been compared in the LFER conceptual framework. •QSAR: empirical model of complexity and complementarity in drug–target interactions. •Selected examples of QSAR models of inhibitor–enzyme complexes are discussed.
Paolo Montuschi, Mario Malerba, Giuseppe Santini, Marc Miravitlles
Highlights
•Several phenotypes characterize chronic obstructive pulmonary disease (COPD). •Response to pharmacological treatment in COPD is highly variable. •Guidelines suggest similar treatment of COPD patients within a severity class. •Pharmacotherapy of COPD is changing from evidence-based to personalized medicine. •This strategy has to be validated in future clinical studies.
Michael Honer, Luca Gobbi, Laurent Martarello, Robert A. Comley
Highlights
• The development of radioligands for imaging of the brain with PET is discussed. • The in vitro and preclinical evaluation of candidate radioligands is described. • Characteristics predictive of good in vivo performance are presented. • The steps involved in evaluating new ligands in humans are described.
Johan J.F. Verhoef, John F. Carpenter, Thomas J. Anchordoquy, Huub Schellekens
Highlights
•PEGylated nanocarriers are linked to the accelerated blood clearance (ABC) phenomenon. •The ABC is induced by anti-PEG antibodies and/or complement activation. •PEGylated proteins can induce complement activation and anti-PEG antibodies. •Anti-PEG antibody data are difficult to interpret because no validated assay exists.
•High ALDH expression in CSCs is associated with a worse prognosis. •ALDH isozyme expression can to some extent be cancer specific. •Rational approach to chemical modulators of ALDH isozymes provides selectivity. •High expression of certain ALDH isozymes provides an opportunity for drug discovery. •An ALDH inhibitor can only be truly effective in combination treatment.
Matteo Castelli, Nicola Clementi, Giuseppe A. Sautto, Jennifer Pfaff, Kristen M. Kahle, Trevor Barnes, Benjamin J. Doranz, Matteo Dal Peraro, Massimo Clementi, Roberto Burioni, Nicasio Mancini
Highlights
•HCV/E2 core (E2c) crystal structures present structural discrepancies. •HCV/E2 conformation and cysteine coupling relies on the experimental setup. •HCV/E2c structures are in partial disagreement with functional data. •Monoclonal antibody reactivity suggests an alternative E2 cysteine coupling.
