Single-target Drugs Research Articles

Carrier-free Chinese herbal small molecules self-assembly with 3D-porous crystal framework as a synergistic anti-AD agent

Alzheimer's disease (AD) is a devastating neurodegenerative disease caused by multiple factors. Single-target drugs have limited efficacy for AD treatment. Therefore, multi-target intervention strategy has great potential. Traditional Chinese medicine (TCM) is mostly used in the form of compound prescription, which has the polypharmacology behavior. Rhizoma Coptidis and Radix et Rhizoma Rhei are frequently used as the couplet medicines of TCM for AD therapy. In this study, the novel carrier-free nanoassembly with 3D-porous frame crystal structure has formulated from supramolecular self-assembly of berberine (BER) and rhein (RHE), the main active components of Rhizoma Coptidis and Radix et Rhizoma Rhei, respectively. Combining with the spectral data and single crystal structure, the self-assembly process was clarified as dominated by electrostatic interaction and π-π stacking. In vitro release property, cholinesterase (ChE) inhibition, β-amyloid (Aβ) aggregation regulation, radical elimination, metal ions chelation and cytotoxicity assay indicated that the obtained BER-RHE assembly had the Fickian diffusion-controlled sustained release ability, synergistic biological activities and virtually no neurotoxicity. In addition, in vivo reactive oxygen species (ROS) level evaluation showed that the assembly could reduce the accumulation of intracellular ROS in Caenorhabditis elegans (C. elegans). Meanwhile, BER-RHE assembly could also be used as a novel potential carrier for drug delivery due to its superior 3D-porous frame. This green and facile strategy for carrier-free nanoassembly microscopic construction via supramolecular self-assembly might provide inspiration for the development of multi-target therapy for AD and the design of the novel drug delivery system.

Medicinal Herbs and Their Derived Ingredients Protect against Cognitive Decline in In Vivo Models of Alzheimer's Disease.

Alzheimer’s disease (AD) has pathological hallmarks including amyloid beta (Aβ) plaque formation. Currently approved single-target drugs cannot effectively ameliorate AD. Medicinal herbs and their derived ingredients (MHDIs) have multitarget and multichannel properties, engendering exceptional AD treatment outcomes. This review delineates how in in vivo models MHDIs suppress Aβ deposition by downregulating β- and γ-secretase activities; inhibit oxidative stress by enhancing the antioxidant activities and reducing lipid peroxidation; prevent tau hyperphosphorylation by upregulating protein phosphatase 2A expression and downregulating glycogen synthase kinase-3β expression; reduce inflammatory mediators partly by upregulating brain-derived neurotrophic factor/extracellular signal-regulated protein kinase 1/2-mediated signaling and downregulating p38 mitogen-activated protein kinase (p38 MAPK)/c-Jun N-terminal kinase (JNK)-mediated signaling; attenuate synaptic dysfunction by increasing presynaptic protein, postsynaptic protein, and acetylcholine levels and preventing acetylcholinesterase activity; and protect against neuronal apoptosis mainly by upregulating Akt/cyclic AMP response element-binding protein/B-cell lymphoma 2 (Bcl-2)-mediated anti-apoptotic signaling and downregulating p38 MAPK/JNK/Bcl-2-associated x protein (Bax)/caspase-3-, Bax/apoptosis-inducing factor-, C/EBP homologous protein/glucose-regulated protein 78-, and autophagy-mediated apoptotic signaling. Therefore, MHDIs listed in this review protect against Aβ-induced cognitive decline by inhibiting Aβ accumulation, oxidative stress, tau hyperphosphorylation, inflammation, synaptic damage, and neuronal apoptosis in the cortex and hippocampus during the early and late AD phases.

Rapid-SL identifies synthetic lethal sets with an arbitrary cardinality

The multidrug resistance of numerous pathogenic microorganisms is a serious challenge that raises global healthcare concerns. Multi-target medications and combinatorial therapeutics are much more effective than single-target drugs due to their synergistic impact on the systematic activities of microorganisms. Designing efficient combinatorial therapeutics can benefit from identification of synthetic lethals (SLs). An SL is a set of non-essential targets (i.e., reactions or genes) that prevent the proliferation of a microorganism when they are “knocked out” simultaneously. To facilitate the identification of SLs, we introduce Rapid-SL, a new multimodal implementation of the Fast-SL method, using the depth-first search algorithm. The advantages of Rapid-SL over Fast-SL include: (a) the enumeration of all SLs that have an arbitrary cardinality, (b) a shorter runtime due to search space reduction, (c) embarrassingly parallel computations, and (d) the targeted identification of SLs. Targeted identification is important because the enumeration of higher order SLs demands the examination of too many reaction sets. Accordingly, we present specific applications of Rapid-SL for the efficient targeted identification of SLs. In particular, we found up to 67% of all quadruple SLs by investigating about 1% of the search space. Furthermore, 307 sextuples, 476 septuples, and over 9000 octuples are found for Escherichia coli genome-scale model, iAF1260.

Research Progress of PARP-1 Related Dual Target Inhibitors

The treatment of cancer has always been based on surgery, radiotherapy and chemotherapy, but the cure rate of these methods is often very low and the side effects on patients are very serious. With the gradual understanding of cancer, targeted drug therapy has gradually attracted the attention of the scientific community. Initially, doctors used some single target inhibitors as targeted drugs for tumor treatment. However, with the increasing of single drug resistance and side effects, the problems of single drug resistance and side effects gradually emerge in clinical practice. Poly ADP-ribose polymerase-1 inhibitor (parp-1i) can inhibit DNA damage and repair in cells, so it is used as a kind of targeted drugs for tumor therapy. At a time when single target drugs are facing challenges, scientists have turned their attention to dual target inhibitors related to parp-1i with stronger effects. In this paper, we focus on the challenges faced by PARP-1 related single target inhibitors and the research progress of HDAC inhibitors or BRD4 inhibitors combined with PARP-1 inhibitors as double target inhibitors. It was found out that some new synthesized dual PARP/HDAC inhibitors and PARP/BRD4 inhibitors have shown great anticancer activities in vitro experiments, including compound I-8 and II-16 Therefore, this review confirmsthat PARP-related dual target inhibitors can be a promising approach to treat cancer cell.

Design Strategies, Chemistry and Therapeutic Insights of Multi-target Directed Ligands as Antidepressant Agents.

Depression is one of the major disorders of the central nervous system worldwide and causes disability and functional impairment. According to the World Health Organization, around 265 million people worldwide are affected by depression. Currently marketed antidepressant drugs take weeks or even months to show anticipated clinical efficacy but remain ineffective in treating suicidal thoughts and cognitive impairment. Due to the multifactorial complexity of the disease, single-target drugs do not always produce satisfactory results and lack the desired level of therapeutic efficacy. Recent literature reports have revealed improved therapeutic potential of multi-target directed ligands due to their synergistic potency and better safety. Medicinal chemists have gone to great extents to design multitarget ligands by generating structural hybrids of different key pharmacophores with improved binding affinities and potency towards different receptors or enzymes. This article has compiled the design strategies of recently published multi-target directed ligands as antidepressant agents. Their biological evaluation, structural-activity relationships, mechanistic and in silico studies have also been described. This article will prove to be highly useful for the researchers to design and develop multi-target ligands as antidepressants with high potency and therapeutic efficacy.

Exploring Ganweikang Tablet as a Candidate Drug for NAFLD Through Network Pharmacology Analysis and Experimental Validation.

Nonalcoholic fatty liver disease (NAFLD) is defined as liver disease in which more than 5% of hepatocytes are steatotic with little or no alcohol consumption. NAFLD includes benign nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). Importantly, NASH is an advanced progression of NAFL and is characterized by steatosis, hepatocyte ballooning, lobular inflammation, and fibrosis. However, to date, no drugs specifically targeting NAFLD have been approved by the FDA. Therefore, a new drug or strategy for NAFLD treatment is necessary. However, the pathogenesis of NAFLD is complex and no single-target drugs have achieved the desired results. Noticeably, traditional Chinese medicine formulations are a complex system with multiple components, multiple targets, and synergistic effects between components. The Ganweikang tablet is a compound formula based on traditional Chinese medicine theory and clinical experience. In this study, network pharmacology analysis indicates Ganweikang tablet as a candidate for NAFLD treatment. Furthermore, we evaluated the therapeutic effects of Ganweikang tablet on the NAFL and NASH and tried to clarify the underlying molecular mechanisms in animal models and cell experiments. As expected, Ganweikang tablet was found to improve NAFL and NASH by modulating inflammation, apoptosis, and fatty acid oxidation by inhibiting NFκB, caspase-8, and activating PPARα, which not only indicates that Ganweikang tablet as a drug candidate but also provides a theoretical basis of Ganweikang tablet for the treatment of NAFL and NASH.

Entrectinib, a new multi-target inhibitor for cancer therapy.

Clinical practice shows that when single-target drugs treat multi-factor diseases such as tumors, cardiovascular system and endocrine system diseases, it is often difficult to achieve good therapeutic effects, and even serious adverse reactions may occur. Multi-target drugs can simultaneously regulate multiple links of disease, improve efficacy, reduce adverse reactions, and improve drug resistance. They are ideal drugs for treating complex diseases, and therefore have become the main direction of drug development. At present, some multi-target drugs have been successfully used in many major diseases. Entrectinib is an oral small molecule inhibitor that targets TRK, ROS1, and ALK. It is used to treat locally advanced or metastatic solid tumors with NTRK1/2/3, ROS1 and ALK gene fusion mutations. It can pass through the blood-brain barrier and is the only TRK inhibitor clinically proven to be effective against primary and metastatic brain diseases. In 2019, entrectinib was approved by the FDA to treat adult patients with ROS1-positive metastatic non-small cell lung cancer. Case reports showed that continuous administration of entrectinib was effective and tolerable. In this review, we give a brief introduction to TKK, ROS1 and ALK, and on this basis, we give a detailed and comprehensive introduction to the mechanism of action, pharmacokinetics, pharmacodynamics, clinical efficacy, tolerability and drug interactions of entrectinib.

What are the challenges with multi-targeted drug design for complex diseases?

ABSTRACT Introduction Current findings on multifactorial diseases with a complex pathomechanism confirm that multi-target drugs are more efficient ways in treating them as opposed to single-target drugs. However, to design multi-target ligands, a number of factors and challenges must be taken into account. Areas covered In this perspective, we summarize the concept of application of multi-target drugs for the treatment of complex diseases such as neurodegenerative diseases, schizophrenia, diabetes, and cancer. We discuss the aspects of target selection for multifunctional ligands and the application of in silico methods in their design and optimization. Furthermore, we highlight other challenges such as balancing affinities to different targets and drug-likeness of obtained compounds. Finally, we present success stories in the design of multi-target ligands for the treatment of common complex diseases. Expert opinion Despite numerous challenges resulting from the design of multi-target ligands, these efforts are worth making. Appropriate target selection, activity balancing, and ligand drug-likeness belong to key aspects in the design of ligands acting on multiple targets. It should be emphasized that in silico methods, in particular inverse docking, pharmacophore modeling, machine learning methods and approaches derived from network pharmacology are valuable tools for the design of multi-target drugs.

Exploring the Therapeutic Potential of Phytochemicals in Alzheimer's Disease: Focus on Polyphenols and Monoterpenes.

Alzheimer’s disease (AD) is a chronic, complex neurodegenerative disorder mainly characterized by the irreversible loss of memory and cognitive functions. Different hypotheses have been proposed thus far to explain the etiology of this devastating disorder, including those centered on the Amyloid-β (Aβ) peptide aggregation, Tau hyperphosphorylation, neuroinflammation and oxidative stress. Nonetheless, the therapeutic strategies conceived thus far to treat AD neurodegeneration have proven unsuccessful, probably due to the use of single-target drugs unable to arrest the progressive deterioration of brain functions. For this reason, the theoretical description of the AD etiology has recently switched from over-emphasizing a single deleterious process to considering AD neurodegeneration as the result of different pathogenic mechanisms and their interplay. Moreover, much relevance has recently been conferred to several comorbidities inducing insulin resistance and brain energy hypometabolism, including diabetes and obesity. As consequence, much interest is currently accorded in AD treatment to a multi-target approach interfering with different pathways at the same time, and to life-style interventions aimed at preventing the modifiable risk-factors strictly associated with aging. In this context, phytochemical compounds are emerging as an enormous source to draw on in the search for multi-target agents completing or assisting the traditional pharmacological medicine. Intriguingly, many plant-derived compounds have proven their efficacy in counteracting several pathogenic processes such as the Aβ aggregation, neuroinflammation, oxidative stress and insulin resistance. Many strategies have also been conceived to overcome the limitations of some promising phytochemicals related to their poor pharmacokinetic profiles, including nanotechnology and synthetic routes. Considering the emerging therapeutic potential of natural medicine, the aim of the present review is therefore to highlight the most promising phytochemical compounds belonging to two major classes, polyphenols and monoterpenes, and to report the main findings about their mechanisms of action relating to the AD pathogenesis.

Gefitinib-Tamoxifen Hybrid Ligands as Potent Agents against Triple-Negative Breast Cancer.

Anticancer drug conjugates may benefit from simultaneous action at two targets potentially overcoming the drawbacks of current cancer treatment, such as insufficient efficacy, high toxicity, and development of resistance. Compared to a combination of two single-target drugs, they may offer an advantage of pharmacokinetic simplicity and fewer drug-drug interactions. Here, we report a series of compounds connecting tamoxifen or endoxifen with the EGFR-inhibitor gefitinib via a covalent linkage. These hybrid ligands retain both ER antagonist activity and EGFR inhibition. The most potent analogues exhibited single-digit nanomolar activities at both targets. The amide-linked endoxifen-gefitinib drug conjugates 17b and 17c demonstrated the most favorable anti-cancer profile in cellular viability assays on MCF7, MDA-MB-231, MDA-MB-468, and BT-549 breast cancer cells. Most importantly, in TNBC cells 17b and 17c displayed nanomolar IC50-values (380 nM - 970 nM) and were superior in their anti-cancer activity compared to their control compounds and combinations thereof.

Berberis lycium fruit extract and its phytoconstituents berberine and rutin mitigate collagen-CFA-induced arthritis (CIA) via improving GSK3β/STAT/Akt/MAPKs/NF-κB signaling axis mediated oxi-inflammation and joint articular damage in murine model.

Rheumatoid arthritis (RA), a chronic auto-immune disease, is often result of persistent and misdirectional inflammation and cannot be effectually resolved by single-target selective drugs. Present study attempted to uncover anti-arthritic efficacy and governing molecular mechanism of BLFE and its phytoconstituents berberine and rutin, with focus on dysregulated oxi-inflammation and structural integrity during articular damage using Collagen II-CFA-induced RA mice model. NMR-based phytometabolomic analysis revealed presence of phenolics and alkaloids such as berberine and rutin. BLFE, rutin and berberine remarkably mitigated Collagen II-CFA-induced disease severity index, articular damage, immune cells influx and pannus formation. An effective decrease in levels of TNF-α, IL-6, IL-1β, IFN-γ, IL-13, IL-17, MMPs, RORγt, Ob-cadherin, Cox-2, iNOS and enhancement in IL-10, IL-4 and IL-5, BMP-6/7 was observed in BLFE, rutin and berberine treatments. Molecular mechanistic analysis demonstrated reduction in expression of p-STAT-1/3, p-PI3K, p-Akt, p-JNK, p-p38, p-IκB, p-NF-κB and β-catenin via BLFE, rutin and berberine. Furthermore, reduced activation of p-ERK and p-GSK3β and enhanced splenic Tregs was only noticed in BLFE and berberine. Thus, the signifying presence of these phytoconstituents could contribute to the above-mentioned findings. These findings imply that BLFE could be beneficial for assuaging deleterious aspects of RA mediated via perturbed inflammation.

Multitargeted anti-infective drugs: resilience to resistance in the antimicrobial resistanceera.

The standard drug discovery paradigm of single molecule – single biological target – single biological effect is perhaps particularly unsuitable for anti-infective drug discovery. This is due to the rapid evolution of resistance likely to be observed with single target drugs. Multitargeted anti-infective drugs are likely to be superior due to their lower susceptibility to target-related resistance mechanisms. Strathclyde minor groove binders are a class of compounds which have been developed by adopting the multitargeted anti-infective drugs paradigm, and their effectiveness against a wide range of pathogenic organisms is discussed. The renaming of this class to Strathclyde nucleic acid binders is also presented due to their likely targets including both DNA and RNA.

The Design and Optimization of Monomeric Multitarget Peptides for the Treatment of Multifactorial Diseases.

Compared with single-target drugs, multitarget drugs may improve the safety and efficacy of the treatment of multifactorial diseases. However, few multitarget drugs are on the market or in clinical trials currently, and multitarget small molecules account for the majority. Compared with multitarget small molecules, multitarget peptides have unique advantages and show good effects in a variety of diseases. This article discusses the design process of multitarget peptides in four aspects, including target combination, peptide selection, lead generation, and lead optimization. In addition, we analyzed in detail the research cases of multitarget peptides for several multifactorial diseases over years, aiming to reveal the trends and insights of the potential uses of multitarget peptides.

Discovery of dual-target ligands binding to beta2-adrenoceptor and cysteinyl-leukotriene receptor for the potential treatment of asthma from natural products derived DNA-encoded library

The design, synthesis, and discovery of dual-target compounds are considered as a promising strategy to develop new drugs with improved safety and efficacy compared with single-target drugs. This necessitates development of the methodologies that enable us to rapidly and accurately achieve the dual-target leads. Applying rosmarinic acid, 18β-glycyrrhetinic acid, rhein, and ferulic acid as template building blocks, we introduced the self-assembling DNA encoded technique to build the library containing 1,000 compounds. These compounds were screened by receptor chromatography with immobilized beta2-adrenoceptor (β2-AR) and cysteinyl-leukotriene receptor (CysLT), whereby we obtained a derivative of 18β-glycyrrhetinic acid (XC267) that specifically binds to the two receptors. In vitro assessment demonstrated the desired binding affinity of 6.57 × 104 M−1 to β2-AR, 2.82 × 104 M−1 to CysLT, and the dissociation rate constant of 7.52 s−1 to β2-AR, 17.2 s−1 to CysLT. Pharmacological examination with ovalbumin-induced mice demonstrated that XC267 significantly reduced the levels of IL-4, IL-13, and IgE after oral administration of 10 mg/kg. By Western blot analysis, we observed an up-regulated expression of β2-AR and a blocked level of CysLT with a dose-dependent manner in pulmonary bronchial. Our results suggest XC627 is a potential candidate to treat asthma by simultaneously regulating the signaling pathway of the two receptors.

New insights into the discovery of drugs for triple-negative breast cancer metastasis

ABSTRACT Introduction Triple-negative breast cancer (TNBC) is of great concern due to its aggressiveness and lack of targeted therapy. For these reasons, TNBC is one of the main causes of death in women, mainly due to metastases. Tumor dissemination has highlighted a set of possible targets, with extensive research into new single-target drugs, in addition to drug repurposing strategies, being undertaken to discover new classes of potential inhibitors of metastasis. Areas covered The authors here describe the main proposed targets and the bases of their pharmacological inhibition with different chemical compounds. The authors also discuss the state-of-the-art from the latest clinical trials and highlight other potential targets for metastatic TNBC. Expert opinion In the last decade, oncology research has changed its focus from primary tumors to moving tumor cells, their products, and to the secondary tumor and its surroundings, for the purpose of finding targets to treat metastasis. Consequently, our comprehension of the complexity of the metastatic process has increased drastically, with, furthermore, the discovery of new potential targets. Although promising, the wide range of strategies is still not effective to suppress TNBC metastasis in terms of increasing patient survival or decreasing the number of metastases. Treating or preventing metastasis continues to be a great challenge.

Discovery of Anticancer Hybrid Molecules by Supervised Machine Learning Models and in Vitro Validation in Drug Resistant Chronic Myeloid Leukemia Cells.

The concept of hybrid drugs for targeting multiple aberrant pathways of cancer, by combining the key pharmacophores of clinically approved single-targeted drugs, has emerged as a promising approach for overcoming drug-resistance. Here, we report the design of unique hybrid molecules by combining the two pharmacophores of clinically approved BCR-ABL inhibitor (ponatinib) and HDAC inhibitor (vorinostat) and results of in vitro studies in drug-resistant CML cells. Robust 2D-QSAR and 3D-pharmacophore machine learning supervised models were developed for virtual screening of the hybrid molecules based on their predicted BCR-ABL and HDAC inhibitory activity. The developed 2D-QSAR model showed five information rich molecular descriptors while the 3D-pharmacophore model of BCR-ABL showed five different chemical features (hydrogen bond acceptor, donor, hydrophobic group, positive ion group, and aromatic rings) and the HDAC model showed four different chemical features (hydrogen bond acceptor, donor, positive ion group, and aromatic rings) for potent BCR-ABL and HDAC inhibition. Virtual screening of the 16 designed hybrid molecules identified FP7 and FP10 with better potential of inhibitory activity. FP7 was the most effective molecule with predicted IC50 using the BCR-ABL based 2D-QSAR model of 0.005 μM and that of the HDAC model of 0.153 μM, and that using the BCR-ABL based 3D-pharmacophore model was 0.02 μM and that with HDAC model was 0.014 μM. In vitro study (dose-response relationship) of FP7 in wild type and imatinib-resistant CML cell lines harboring Thr315Ile or Tyr253His mutations showed growth inhibitory IC50 values of 0.000 16, 0.0039, and 0.01 μM, respectively. This molecule also showed better biocompatibility when tested in whole blood and in PBMCs as compared to ponatinib or vorinostat.

Identification of novel dual inhibitors targeting XOR and URAT1 via multiple virtual screening methods

The clinically applicable single uric acid transporter 1 (URAT1) inhibitor or xanthine oxidoreductase (XOR) inhibitor cannot solve the clinical needs in anti-hyperuricemia well. It is expected that combined inhibition of both XOR and URAT1 might effectively decrease the level of uric acid and avoid the issue of insufficient potency by single-target drugs. 3D-QSAR pharmacophore modeling, molecular docking, and ADMET filtering were applied for potential dual inhibitors. And top-ranked three compounds were selected to MD simulation analysis, with utilization of binding free energy and decomposition data. 4917-2281, 4109-2078 and C301-8913, have potential inhibitory potency for both XOR and URAT1 and were suitable for further experimental analysis and modification.

Molecular Modeling Techniques Applied to the Design of Multitarget Drugs: Methods and Applications

Multifactorial diseases, such as cancer and diabetes present a challenge for the traditional "one-target, one disease" paradigm due to their complex pathogenic mechanisms. Although a combination of drugs can be used, a multitarget drug may be a better choice due to its efficacy, lower adverse effects and lower chance of resistance development. The computer-based design of these multitarget drugs can explore the same techniques used for single-target drug design, but the difficulties associated with the obtention of drugs that are capable of modulating two or more targets with similar efficacy impose new challenges, whose solutions involve the adaptation of known techniques and also to the development of new ones, including machine-learning approaches. In this review, some SBDD and LBDD techniques for the multitarget drug design are discussed, together with some cases where the application of such techniques led to effective multitarget ligands.

Medicine-Food Herbs against Alzheimer’s Disease: A Review of Their Traditional Functional Features, Substance Basis, Clinical Practices and Mechanisms of Action

Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder that currently has reached epidemic proportions among elderly populations around the world. In China, available traditional Chinese medicines (TCMs) that organically combine functional foods with medicinal values are named “Medicine Food Homology (MFH)”. In this review, we focused on MFH varieties for their traditional functional features, substance bases, clinical uses, and mechanisms of action (MOAs) for AD prevention and treatment. We consider the antiAD active constituents from MFH species, their effects on in vitro/in vivo AD models, and their drug targets and signal pathways by summing up the literature via a systematic electronic search (SciFinder, PubMed, and Web of Science). In this paper, several MFH plant sources are discussed in detail from in vitro/in vivo models and methods, to MOAs. We found that most of the MFH varieties exert neuroprotective effects and ameliorate cognitive impairments by inhibiting neuropathological signs (Aβ-induced toxicity, amyloid precursor protein, and phosphorylated Tau immunoreactivity), including anti-inflammation, antioxidative stress, antiautophagy, and antiapoptosis, etc. Indeed, some MFH substances and their related phytochemicals have a broad spectrum of activities, so they are superior to simple single-target drugs in treating chronic diseases. This review can provide significant guidance for people’s healthy lifestyles and drug development for AD prevention and treatment.

Anti-allergic, anti-asthmatic and anti-inflammatory effects of an oxazolidinone hydroxamic acid derivative (PH-251) – A novel dual inhibitor of 5-lipoxygenase and mast cell degranulation

We have recently reported the discovery of a series of oxazolidinone hydroxamic acid derivatives that are potent inhibitors of 5-lipoxygenase (5-LO) [arachidonate 5-lipoxygenase; EC 1.13.11.34]. We now report that one of the most active members of this series, compound PH-251, [(R)-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl) methyl)-N-hydroxyoctanamide], also possesses a unique and strong ability to concurrently inhibit mast cell degranulation. PH-251 inhibited the biosynthesis of leukotriene C4 (LTC4), as well as degranulation of IgE/allergen-activated bone marrow-derived mouse mast cells (BMMC) in vitro. In contrast, zileuton (the prototype 5-LO inhibitor) inhibited leukotriene generation, but not degranulation. Consistent with its dual activity, compound PH-251 also significantly inhibited both the early and the late anaphylactic contractions of guinea pig lung parenchymal strip, whereas zileuton inhibited only the late (leukotriene-dependent) contractions. Comparative structure–activity analysis of PH-251 and its structural analogues showed that the anti-degranulation effect appeared to be dependent on the length of the straight-chain hydrocarbon substitution on the hydroxamic acid moiety. In the in vivo studies, PH-251 (3–30 mg/kg s.c.) strongly inhibited various components of zymosan-induced peritonitis - a typical non-allergic LT-dependent animal model of inflammation. In the mouse allergic asthma model, the compound significantly inhibited allergen-induced bronchial eosinophilic inflammation and airway hyper-responsiveness to inhaled methacholine. These results show that PH-251 is a unique dual inhibitor of 5-LO and mast cell degranulation, with in vivo activity in animal models of disease and may therefore offer potential advantages over single-target drugs in the treatment of asthma and other allergic and inflammatory diseases.