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Summary Purpose This phase I trial assessed the safety, dose limiting toxicity (DLT) and pharmacodynamics of PX-12 in adult patients with advanced refractory cancers. Methods PX-12 was administered to sequential cohorts as a 72-h infusion utilizing a portable infusion pump on days 1, 2, and 3 of a 21-day cycle at a starting dose level of 300 mg/m 2 /day and escalating dose levels till DLT was observed. Plasma thioredoxin (Trx-1), vascular endothelial growth factor (VEGF) and FGF-2 (fibroblast growth factor) levels were measured predose and during infusion of PX-12. Results Patients ( n  = 14) were enrolled to the following dose cohorts, 300 mg/m 2 ( n  = 3), 400 mg/m 2 ( n  = 10) and 500 mg/m 2 ( n  = 1). Common grade 1/2 toxicities included fatigue, taste alteration and odor caused by expired drug metabolite. DLTs were one episode each of grade 3 hypoxia at the 400 mg/m 2 and grade 3 reversible pneumonitis at the 500 mg/m 2 dose levels. Best response was stable disease in a patient with rectal cancer. Predose Trx-1 levels ( n  = 12) ranged from 5.1 to 30.0 ng/mL (median 12.6 ng/mL). Conclusion PX-12 administered at 400 mg/m 2 /day by 72-hour infusion appears safe and tolerable. Inhibition of thioredoxin is a strategy worth evaluation with next generation of inhibitors.

To be effective as a drug, a potent molecule must reach its target in the body in sufficient concentration, and stay there in a bioactive form long enough for the expected biologic events to occur. Drug development involves assessment of absorption, distribution, metabolism and excretion (ADME) increasingly earlier in the discovery process, at a stage when considered compounds are numerous but access to the physical samples is limited. In that context, computer models constitute valid alternatives to experiments. Here, we present the new SwissADME web tool that gives free access to a pool of fast yet robust predictive models for physicochemical properties, pharmacokinetics, drug-likeness and medicinal chemistry friendliness, among which in-house proficient methods such as the BOILED-Egg, iLOGP and Bioavailability Radar. Easy efficient input and interpretation are ensured thanks to a user-friendly interface through the login-free website http://www.swissadme.ch . Specialists, but also nonexpert in cheminformatics or computational chemistry can predict rapidly key parameters for a collection of molecules to support their drug discovery endeavours.

The use of in silico toxicity prediction methods plays an important role in the selection of lead compounds and in ADMET studies since in vitro and in vivo methods are often limited by ethics, time, budget and other resources. In this context, we present our new web tool VenomPred, a user-friendly platform for evaluating the potential mutagenic, hepatotoxic, carcinogenic and estrogenic effects of small molecules. VenomPred platform employs several in-house Machine Learning (ML) models developed with datasets derived from VEGA QSAR, a software that includes a comprehensive collection of different toxicity models and has been used as a reference for building and evaluating our ML models. The results showed that our models achieved equal or better performance than those obtained with the reference models included in VEGA QSAR. In order to improve the predictive performance of our platform, we adopted a consensus approach combining the results of different ML models, which was able to predict chemical toxicity better than the single models. This improved method was thus implemented in the VenomPred platform, a freely accessible webserver that takes the SMILES (Simplified Molecular-Input Line-Entry System) strings of the compounds as input and sends the prediction results providing a probability score about their potential toxicity.

Advances in harnessing the immune system for cancer treatment have been spectacular in recent years as witnessed by the approval of a number of antibodies targeting the PD-1/PD-L1 immune checkpoint pathway spanning an expanding list of indications. However, it is well recognized that while these antibodies show impressive clinical activity, they suffer from shortcomings including the failure to show response in a majority of patients, their need to be administered by intravenous injection, and immune-related adverse events due to the breaking of immune self-tolerance. Small-molecule-based therapeutic approaches offer the potential to address the shortcomings of these antibody-based checkpoint inhibitors. In the first part of this review, we discuss the rationale for small-molecule-based checkpoint therapy followed by efforts on the discovery of small-molecule-based approaches targeting the PD-1/PD-L1 axis and other immune checkpoint pathways. In the latter part of the article, we describe small-molecule inhibitors simultaneously targeting two non-redundant checkpoint inhibitor pathways as an approach to improve the response rate. A brief review of the progress of an oral small-molecule checkpoint inhibitor currently in clinical development is presented at the end.

Membrane proteins constitute a substantial fraction of the human proteome, thus representing a vast source of therapeutic drug targets. Indeed, newly devised technologies now allow targeting “undruggable” regions of membrane proteins to modulate protein function in the cell. Despite the advances in technology, the rapid translation of basic science discoveries into potential drug candidates targeting transmembrane protein domains remains challenging. We address this issue by harmonizing single molecule-based and ensemble-based atomistic simulations of ligand–membrane interactions with patient-derived induced pluripotent stem cell (iPSC)-based experiments to gain insights into drug delivery, cellular efficacy, and safety of molecules directed at membrane proteins. In this study, we interrogated the pharmacological activation of the cardiac Ca 2+ pump (Sarcoplasmic reticulum Ca 2+ -ATPase, SERCA2a) in human iPSC-derived cardiac cells as a proof-of-concept model. The combined computational-experimental approach serves as a platform to explain the differences in the cell-based activity of candidates with similar functional profiles, thus streamlining the identification of drug-like candidates that directly target SERCA2a activation in human cardiac cells. Systematic cell-based studies further showed that a direct SERCA2a activator does not induce cardiotoxic pro-arrhythmogenic events in human cardiac cells, demonstrating that pharmacological stimulation of SERCA2a activity is a safe therapeutic approach targeting the heart. Overall, this novel multiscale platform encompasses organ-specific drug potency, efficacy, and safety, and opens new avenues to accelerate the bench-to-patient research aimed at designing effective therapies directed at membrane protein domains.

Toxicity is a major cause of failure in drug discovery and development, and whilst robust toxicological testing occurs, efficiency could be improved if compounds with cytotoxic characteristics were identified during primary compound screening. The use of high-content imaging in primary screening is becoming more widespread, and by utilising phenotypic approaches it should be possible to incorporate cytotoxicity counter-screens into primary screens. Here we present a novel phenotypic assay that can be used as a counter-screen to identify compounds with adverse cellular effects. This assay has been developed using U2OS cells, the PerkinElmer Operetta high-content/high-throughput imaging system and Columbus image analysis software. In Columbus, algorithms were devised to identify changes in nuclear morphology, cell shape and proliferation using DAPI, TOTO-3 and phosphohistone H3 staining, respectively. The algorithms were developed and tested on cells treated with doxorubicin, taxol and nocodazole. The assay was then used to screen a novel, chemical library, rich in natural product-like molecules of over 300 compounds, 13.6% of which were identified as having adverse cellular effects. This assay provides a relatively cheap and rapid approach for identifying compounds with adverse cellular effects during screening assays, potentially reducing compound rejection due to toxicity in subsequent in vitro and in vivo assays.

Safety pharmacology screening against a wide range of unintended vital targets using in vitro assays is crucial to understand off-target interactions with drug candidates. With the increasing demand for in vitro assays, ligand- and structure-based virtual screening approaches have been evaluated for potential utilization in safety profiling. Although ligand based approaches have been actively applied in retrospective analysis or prospectively within well-defined chemical space during the early discovery stage (i.e., HTS screening and lead optimization), virtual screening is rarely implemented in later stage of drug discovery (i.e., safety). Here we present a case study to evaluate ligand-based 3D QSAR models built based on in vitro antagonistic activity data against adenosine receptor 2A (A2A). The resulting models, obtained from 268 chemically diverse compounds, were used to test a set of 1,897 chemically distinct drugs, simulating the real-world challenge of safety screening when presented with novel chemistry and a limited training set. Due to the unique requirements of safety screening versus discovery screening, the limitations of 3D QSAR methods (i.e., chemotypes, dependence on large training set, and prone to false positives) are less critical than early discovery screen. We demonstrated that 3D QSAR modeling can be effectively applied in safety assessment prior to in vitro assays, even with chemotypes that are drastically different from training compounds. It is also worth noting that our model is able to adequately make the mechanistic distinction between agonists and antagonists, which is important to inform subsequent in vivo studies. Overall, we present an in-depth analysis of the appropriate utilization and interpretation of pharmacophore-based 3D QSAR models for safety screening.

Growing evidence has demonstrated a neuroprotective role of autophagy in Alzheimer's disease (AD). Thus, autophagy has been regarded as a potential therapeutic target, attracting increasing interest in pharmaceutical autophagy modulation by small molecules. We designed a two-cycle screening strategy on the basis of imaging high-throughout screening (HTS) and cellular toxicity assay, and have identified a novel autophagy inducer known as GTM-1. We further showed that GTM-1 exhibits dual activities, such as autophagy induction and antagonism against Aβ-oligomer toxicity. GTM-1 modulates autophagy in an Akt-independent and mTOR-independent manner. In addition, we demonstrated that GTM-1 enhances autophagy clearance and reverses the downregulation of autophagy flux by thapsigargin and asparagine. Furthermore, administration of GTM-1 attenuated Aβ pathology and ameliorated cognitive deficits in AD mice.

Duchenne muscular dystrophy (DMD) is a devastating muscle wasting disease caused by mutations in dystrophin, a muscle cytoskeletal protein. Utrophin is a homologue of dystrophin that can functionally compensate for its absence when expressed at increased levels in the myofibre, as shown by studies in dystrophin-deficient mice. Utrophin upregulation is therefore a promising therapeutic approach for DMD. The use of a small, drug-like molecule to achieve utrophin upregulation offers obvious advantages in terms of delivery and bioavailability. Furthermore, much of the time and expense involved in the development of a new drug can be eliminated by screening molecules that are already approved for clinical use. We developed and validated a cell-based, high-throughput screening assay for utrophin promoter activation, and used it to screen the Prestwick Chemical Library of marketed drugs and natural compounds. Initial screening produced 20 hit molecules, 14 of which exhibited dose-dependent activation of the utrophin promoter and were confirmed as hits. Independent validation demonstrated that one of these compounds, nabumetone, is able to upregulate endogenous utrophin mRNA and protein, in C2C12 muscle cells. We have developed a cell-based, high-throughput screening utrophin promoter assay. Using this assay, we identified and validated a utrophin promoter-activating drug, nabumetone, for which pharmacokinetics and safety in humans are already well described, and which represents a lead compound for utrophin upregulation as a therapy for DMD.

Summary PAC-1 is a preferential small molecule activator of procaspase-3 and has potential to become a novel and effective anticancer agent. The rational development of PAC-1 for translational oncologic applications would be advanced by coupling relevant in vitro cytotoxicity studies with pharmacokinetic investigations conducted in large mammalian models possessing similar metabolism and physiology as people. In the present study, we investigated whether concentrations and exposure durations of PAC-1 that induce cytotoxicity in lymphoma cell lines in vitro can be achievable in healthy dogs through a constant rate infusion (CRI) intravenous delivery strategy. Time- and dose-dependent procaspase-3 activation by PAC-1 with subsequent cytotoxicity was determined in a panel of B-cell lymphoma cells in vitro. The pharmacokinetics of PAC-1 administered orally or intravenously was studied in 6 healthy dogs using a crossover design. The feasibility of maintaining steady state plasma concentration of PAC-1 for 24 or 48 h that paralleled in vitro cytotoxic concentrations was investigated in 4 healthy dogs. In vitro, PAC-1 induced apoptosis in lymphoma cell lines in a time- and dose-dependent manner. The oral bioavailability of PAC-1 was relatively low and highly variable (17.8 ± 9.5%). The achievement and maintenance of predicted PAC-1 cytotoxic concentrations in normal dogs was safely attained via intravenous CRI lasting for 24 or 48 h in duration. Using the dog as a large mammalian model, PAC-1 can be safely administered as an intravenous CRI while achieving predicted in vitro cytotoxic concentrations.