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Direct and selective pharmacological disruption of the YAP-TEAD interface inhibits cancers with genetic alterations in the Hippo and RAS-MAPK pathways
No full textYAP-TEAD protein-protein interaction is a crucial event known to mediate YAP oncogenic functions downstream of the Hippo pathway. Here we present IAG933, the first molecule able to potently disrupt YAP/TAZ and TEADs protein-protein interaction with suitable properties to enter clinical trials. Biochemical and cellular assays demonstrate specific abrogation of the interaction between YAP/TAZ coactivators and all four TEAD isoforms. Direct pharmacological disruption leads to YAP eviction from chromatin, and consequent engagement of TEADs co-repressor VGLL4. with concomitant decrease in Hippo-related transcriptional activity thereby inducing cancer cell killing. Compound selectivity was shown in rescue experiments, consistent with the correlation observed between pharmacological and genetic sensitivity profiles. In preclinical experiments, deep tumor regression is observed in mesothelioma xenograft models, at doses tolerated in both mice and rats. IAG933 anti-tumor efficacy is also observed in other Hippo-mutated cancer models as well as in combination with RTK, RAS, RAF and MAPK inhibitors, in non-Hippo altered models including lung, pancreatic and colorectal cancer. Overall, our results provide a robust rationale of using IAG933 as monotherapy or combination therapy, with the potential to treat various patient populations with high unmet medical need
Greener Methodologies in Organic Chemistry: A Pathway Towards Sustainable Future
No full textImplementing green chemistry practices has resulted in improved environmental safety and cost efficiency in various pharmaceutical processes, significantly reducing toxic waste production. In this regard, organic solvents are a prominent component of organic reactions and contribute significantly to hazardous waste generation. In contrast, water is a sustainable alternative that serves as a stable, benign, and environmentally friendly solvent. Micellar catalysis using designer surfactants has significantly enhanced water's effectiveness as a solvent in organic synthesis. These surfactant molecules have a unique architecture that improves water's solubility and acts as an initiator or stabilizer for nanoparticles, resulting in efficient catalysis. Micelles also serve as nanoreactors with a high local concentration of reactants, resulting in unprecedented reaction rates and excellent selectivity. Many sustainable protocols using aqueous micellar chemistry in pharmaceutical synthesis have proven highly effective and are discussed in this review. Furthermore, this review will discuss the incorporation of nanocatalysis with earth-abundant first-row transition metals and the role of surfactants as a nanoparticle catalyst stabilizer. The role of specially designed proline-based surfactant PS-750-M as a ligand or capping agent enabling ligand-free metal nanocatalysis is also highlighted. Finally, the review outlines the present challenges and future directions in green chemistry, emphasizing the need for continued research and innovation to promote sustainable and eco-friendly practices benefitting the pharmaceutical industry
Mobilise-D insights to estimate real-world walking speed in multiple conditions with a wearable device.
No full textThis study aimed to validate a wearable device's walking speed estimation pipeline, considering complexity, speed, and walking bout duration. The goal was to provide recommendations on the use of wearable devices for real-world mobility analysis. Participants with Parkinson's Disease, Multiple Sclerosis, Proximal Femoral Fracture, Chronic Obstructive Pulmonary Disease, Congestive Heart Failure, and healthy older adults (n = 97) were monitored in the laboratory and the real-world (2.5 h), using a lower back wearable device. Two walking speed estimation pipelines were validated across 4408/1298 (2.5 h/laboratory) detected walking bouts, compared to 4620/1365 bouts detected by a multi-sensor reference system. In the laboratory, the mean absolute error (MAE) and mean relative error (MRE) for walking speed estimation ranged from 0.06 to 0.12 m/s and - 2.1 to 14.4%, with ICCs (Intraclass correlation coefficients) between good (0.79) and excellent (0.91). Real-world MAE ranged from 0.09 to 0.13, MARE from 1.3 to 22.7%, with ICCs indicating moderate (0.57) to good (0.88) agreement. Lower errors were observed for cohorts without major gait impairments, less complex tasks, and longer walking bouts. The analytical pipelines demonstrated moderate to good accuracy in estimating walking speed. Accuracy depended on confounding factors, emphasizing the need for robust technical validation before clinical application.Trial registration: ISRCTN - 12246987
Novel Inhibitory Site Revealed by XAP044 Mode of Action on the Metabotropic Glutamate 7 Receptor Venus Flytrap Domain.
No full textMetabotropic glutamate (mGlu) receptors play a key role in modulating most synapses in the brain. The mGlu7 receptors inhibit presynaptic neurotransmitter release and offer therapeutic possibilities for post-traumatic stress disorders or epilepsy. Screening campaigns provided mGlu7-specific allosteric modulators as the inhibitor XAP044 (Gee et al. J. Biol. Chem. 2014). In contrast to other mGlu receptor allosteric modulators, XAP044 does not bind in the transmembrane domain but to the extracellular domain of the mGlu7 receptor and not at the orthosteric site. Here, we identified the mode of action of XAP044, combining synthesis of derivatives, modeling and docking experiments, and mutagenesis. We propose a unique mode of action of these inhibitors, preventing the closure of the Venus flytrap agonist binding domain. While acting as a noncompetitive antagonist of L-AP4, XAP044 and derivatives act as apparent competitive antagonists of LSP4-2022. These data revealed more potent XAP044 analogues and new possibilities to target mGluRs
Use of virtual control groups in nonclinical toxicity studies: the anatomic pathology perspective
No full textIn the last decade, numerous initiatives have emerged worldwide to reduce the use of animals in drug development, including more recently the introduction of Virtual Control Groups (VCGs) concept for nonclinical toxicity studies1. Although replacement of concurrent controls (CC) by virtual controls (VC’s) represents an exciting opportunity, there are associated challenges that will be discussed in this paper with a more specific focus on Anatomic Pathology. Coordinated efforts will be needed from toxicologists, clinical and anatomic pathologists, and regulators to support approaches that will facilitate a staggered implementation of VCGs in nonclinical toxicity studies required for submission of new drug candidates. Notably, the authors believe that a validated database for VC animals will need to include histopathology (digital) slides for microscopic assessment. The authors discuss a hybrid approach, whereby control groups are comprised of both concurrent and virtual controls in order to demonstrate proof of concept. Once confidence is established by regulators and sponsors, VC’s will replace some or all concurrent control animals
Risk-based approach to setting sterile filtration microbial bioburden limits - Focus on biotech-derived products.
No full textHolistic concepts should be applied that reduce risks prior to final bioburden testing and sterile filtration, based on enhanced process and product attribute understanding, which could be key to successful bioburden risk management. Key findings of this paper include
Design of greener drugs: aligning parameters in pharmaceutical R&D and drivers for environmental impact.
No full textActive pharmaceutical ingredients (APIs) in the environment, primarily resulting from patient excretion, are of concern because of potential risks to wildlife. This has led to more restrictive regulatory policies. Here, we discuss the 'benign-by-design' approach, which encourages the development of environmentally friendly APIs that are also safe and efficacious for patients. We explore the challenges and opportunities associated with identifying chemical properties that influence the environmental impact of APIs. Although a straightforward application of greener properties could hinder the development of new drugs, more nuanced approaches could lead to drugs that benefit both patients and the environment. We advocate for an enhanced dialogue between research and development (R&D) and environmental scientists and development of a toolbox to incorporate environmental sustainability in drug development
Selecting a randomization method for a multi-center clinical trial with stochastic recruitment considerations.
No full textThe design of a multi-center randomized controlled trial (RCT) involves multiple considerations, such as the choice of the sample size, the number of centers and their geographic location, the strategy for recruitment of study participants, amongst others. There are plenty of methods to sequentially randomize patients in a multi-center RCT, with or without considering stratification factors. The goal of this paper is to perform a systematic assessment of such randomization methods for a multi-center 1:1 RCT assuming a competitive policy for the patient recruitment process.We considered a Poisson-gamma model for the patient recruitment process with a uniform distribution of center activation times. We investigated 16 randomization methods (4 unstratified, 4 region-stratified, 4 center-stratified, 3 dynamic balancing randomization (DBR), and a complete randomization design) to sequentially randomize n = 500 patients. Statistical properties of the recruitment process and the randomization procedures were assessed using Monte Carlo simulations. The operating characteristics included time to complete recruitment, number of centers that recruited a given number of patients, several measures of treatment imbalance and estimation efficiency under a linear model for the response, the expected proportions of correct guesses under two different guessing strategies, and the expected proportion of deterministic assignments in the allocation sequence.Maximum tolerated imbalance (MTI) randomization methods such as big stick design, Ehrenfest urn design, and block urn design result in a better balance-randomness tradeoff than the conventional permuted block design (PBD) with or without stratification. Unstratified randomization, region-stratified randomization, and center-stratified randomization provide control of imbalance at a chosen level (trial, region, or center) but may fail to achieve balance at the other two levels. By contrast, DBR does a very good job controlling imbalance at all 3 levels while maintaining the randomized nature of treatment allocation. Adding more centers into the study helps accelerate the recruitment process but at the expense of increasing the number of centers that recruit very few (or no) patients-which may increase center-level imbalances for center-stratified and DBR procedures. Increasing the block size or the MTI threshold(s) may help obtain designs with improved randomness-balance tradeoff.The choice of a randomization method is an important component of planning a multi-center RCT. Dynamic balancing randomization with carefully chosen MTI thresholds could be a very good strategy for trials with the competitive policy for patient recruitment
Utility and impact of quantitative pharmacology on dose selection and clinical development of immuno-oncology therapy
No full textImmuno-oncology (IO) therapies have changed the cancer treatment landscape. Immune checkpoint inhibitors (ICIs) have improved overall survival in 20-40% of patients with malignancies that were previously refractory. Due to the uniqueness in biology, modalities and patient responses, drug development strategies for IO differed from that traditionally used for cytotoxic and target therapies in oncology, and quantitative pharmacology utilizing modeling approach can be applied in all phases of the development process. In this review, we used case studies to showcase how various modeling methodologies were applied from translational science and dose selection through to label change, using examples that included anti-programmed-death-1 (anti-PD1), anti-programmed-death ligand-1 (anti-PD-L1), anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4), and anti-GITR antibodies. How these approaches were utilized to support phase I-III dose selection, the design of phase III trials, and regulatory decisions on label change are discussed to illustrate development strategies. Model-based quantitative approaches have positively impacted IO drug development, and a better understanding of the biology and exposure-response relationship may benefit the development and optimization of new IO therapies
A promising pipeline of preclinical drug candidates for leishmaniasis and chronic Chagas disease
No full textIn recent years, the drug discovery pipeline for leishmaniasis and trypanosomiasis has been filling with a number of novel chemical entities (NCE) with known mechanisms of action (MoA). Recent work from González [1] and Braillard et al. [2] reports a Cytochrome bc1 complex inhibitor as another promising preclinical candidate for visceral leishmaniasis (VL) and in combination with a current drug, benznidazole, for chronic Chagas disease (CCD)