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CAIN457A2223 12 week microarray data for upload to dbGaP
No full textA paper to publish the CAIN457A2223 12 week data is in preparation and will include the respective microarray data. Publication will require uploading the data to dbGaP, and here we wish to make sure that the data meant for the upload can in fact be made public
Development of a virtual reality platform for effective communication of structural data in drug discovery
No full textIn drug discovery, structural knowledge of a target enables structure-based design approaches and thereby reduces the time and labor required to develop a therapy. Whilst molecular graphics frameworks coupled with computational analysis are now ubiquitous tools for the structural and computational biologist, sharing the detailed visualization and derived structural information with non-expert users still presents a challenge. Here we describe an intuitive virtual world for viewing, manipulating, and modifying chemical and macromolecular structures in a fully immersive and collaborative 3D environment. By reducing the barriers to viewing and interacting with structural data, structural analysis can be democratized to a general scientist, which in turn fosters novel collaboration, ideas, and findings in structural biology and structure-based drug discovery
c-Kit-positive ILC2s exhibit an ILC3-like signature that may contribute to IL-17-mediated pathologies
No full textHere we identify a group 2 innate lymphoid cell (ILC2) subpopulation that can convert into interleukin-17 (IL-17)-producing NKp44− ILC3-like cells. c-Kit and CCR6 define this ILC2 subpopulation that exhibits ILC3 features, including RORγt, enabling the conversion into IL-17-producing cells in response to IL-1β and IL-23. We also report a role for transforming growth factor-β in promoting the conversion of c-Kit− ILC2s into RORγt-expressing cells by inducing the upregulation of IL23R, CCR6 and KIT messenger RNA in these cells. This switch was dependent on RORγt and the downregulation of GATA-3. IL-4 was able to reverse this event, supporting a role for this cytokine in maintaining ILC2 identity. Notably, this plasticity has physiological relevance because a subset of RORγt+ ILC2s express the skin-homing receptor CCR10, and the frequencies of IL-17-producing ILC3s are increased at the expense of ILC2s within the lesional skin of patients with psoriasis
Natural product drug delivery: A special challenge?
No full textNatural products have a long-standing and critical role in drug development and medical use. The structural and physicochemical properties of natural products, while derived evolutionarily to be effective in living systems, may create challenges in translation to a pharmaceutical product. Molecular complexity, low solubility, functional group reactivity and general instability are among the challenges that typically need to be overcome. This review looks at some of the ways that natural products have been formulated and delivered to enable the successful application of these vitally important medicines to patients
Dual Inhibition of MDM2 and MDM4 in Virus-Positive Merkel Cell Carcinoma Enhances the p53 Response
No full textMerkel cell polyomavirus (MCV) contributes to approximately 80%
of all Merkel cell carcinomas (MCC), a highly aggressive neuroendocrine
carcinoma of the skin. MCV-positive MCC expresses small
T antigen (ST) and a truncated form of large T antigen (LT) and
usually contains wild type p53 (TP53) and RB (RB1). In contrast,
virus-negative MCC contains inactivating mutations in TP53 and RB1.
While the MCV truncated LT can bind and inhibit RB, it does not bind
p53. We report here that MCV LT binds to RB leading to increased
levels of ARF, an inhibitor of MDM2, and activation of p53. However,
co-expression of ST reduced p53 activation.
MCV ST recruits the MYC homologue MYCL (L-Myc) to the
EP400 chromatin remodeler complex and transactivates specific target
genes. We observed that depletion of EP400 in MCV-positive
MCC cell lines led to increased p53 target gene expression. We
suspected that the MCV ST-MYCL-EP400 complex could functionally
inactivate p53 but the underlying mechanism was not known. Integrated
ChIP and RNA-seq analysis following EP400 depletion identified
MDM2 as well as CK1�, an activator of MDM4, as target genes
of the ST-MYCL-EP400 complex. In addition, MCV-positive MCC cells
expressed high levels of MDM4. Combining MDM2 inhibitors with
lenalidomide targeting CK1� or an MDM4 inhibitor caused synergistic
activation of p53 leading to an apoptotic response in MCV-positive
MCC cells and MCC-derived xenografts in mice. These results support
dual targeting of MDM2 and MDM4 in virus-positive MCC and
other p53 wild type tumors
Introduction to Digital Image Analysis in Whole-Slide Imaging: A White Paper from the Digital Pathology Association
No full textThe advent of whole-slide imaging in digital pathology has brought about the advancement of computer-aided examination of tissue via digital image analysis. Digitized slides can now be easily annotated and analyzed via a variety of algorithms. This paper reviews the fundamentals of tissue image analysis, and aims to provide pathologists with basic information regarding the features, applications, and general workflow of these new tools. The review gives an overview of the basic categories of software solutions available, potential analysis strategies, technical considerations and general algorithm readouts. Advantages and limitations of tissue image analysis are discussed and emerging concepts, such as artificial intelligence and machine learning, are introduced. Lastly, examples of how digital image analysis is currently being used in diagnostic laboratories, translational research and drug development are discussed
Adhesion G protein-coupled receptors: opportunities for drug discovery
No full textThe seminal discovery of the novel activation mechanism of Adhesion GPCRs (aGPCRs)1,2, together with their strong and growing links to disease from human genetics and pre-clinical research, has prompted a rapid reconsideration of this unique family of receptors for classical drug discovery. However, while acknowledged as a sub-family of GPCRs by the IUPHAR3, these receptors are anything but classical with their complex gene structures, large multi-domain N-termini, autocatalytic cleavage and tethered ligands. Initially thought to have a purely structural role, the increasing functional complexity of this GPCR sub-family and the many, potentially unique mechanisms of modulation challenges the way we have perceived this protein class until now. Significantly, if 50% of non-sensory GPCRs are unexploited as drug targets4, this figure reaches 100% for aGPCRs so the potential to develop novel therapies could be substantial5. Here, we discuss the unique opportunities and challenges brought by aGPCRs in the context of drug discovery programs naturally starting with target identification then extending to target validation, assay building and safety considerations
6-Amino-3-methylpyrimidinones as Potent, Selective, and Orally Efficacious SHP2 Inhibitors
No full textProtein tyrosine phosphatase SHP2 is an oncoprotein associated with cancer as well as a potential immune modulator because of its role in the programmed cell death PD-L1/PD-1 pathway. In the preceding manuscript, we described the optimization of a fused, bicyclic screening hit for potency, selectivity, and physicochemical properties in order to further expand the chemical diversity of allosteric SHP2 inhibitors. In this manuscript, we describe the further expansion of our approach, morphing the fused, bicyclic system into a novel monocyclic pyrimidinone scaffold through our understanding of SAR and use of structure-based design. These studies led to the identification of SHP394 (1), an orally efficacious inhibitor of SHP2, with high lipophilic efficiency, improved potency, and enhanced pharmacokinetic properties. We also report other pyrimidinone analogues with favorable pharmacokinetic and potency profiles. Overall, this work improves upon our previously described allosteric inhibitors and exemplifies and extends the range of permissible chemical templates that inhibit SHP2 via the allosteric mechanism
How to Computationally Stack the Deck for Hit-to-Lead Generation: In Silico Molecular Interaction Energy Profiling for De Novo siRNA Guide Strand Surrogate Selection
No full textThe Argonaute-2 protein is part of the RNA-induced silencing complex (RISC) and anchors the guide strand of the small interfering RNA (siRNA). The 3' end of the RNA contains two unpaired nucleotides (3'-overhang) that interact with the PAZ (PIWI-Argonaute-Zwille) domain of the protein. Theoretical and experimental evidence points towards a direct connection between the PAZ/3'-overhang binding affinity and siRNA's potency and specificity. Among the challenges to overcome when deploying siRNA molecules as therapeutics are their ready degradation under physiological conditions, and off-target effects. It has been demonstrated that nuclease resistance can be improved via replacement of the dinucleotide overhang by small molecules which retain the interactions of the RNA guide strand with the PAZ domain. Most commonly, nucleotide analogues are used to substitute the siRNA overhang. However, in this study we adopt a de novo approach to its modification. The X-ray structure of human Argonaute-2 PAZ domain served to perform virtual screening and molecular interaction energy profiling (i.e., decomposition of the force field calculated protein-ligand interaction energies) of tailored-to-purpose fragment libraries. The binding of fragments to the PAZ domain was validated experimentally by NMR spectroscopy. The in silico guided protocol led to the efficient discovery of a number of PAZ domain ligands with affinities comparable to that of a reference dinucleotide (UpU, Kd = 33 µM). Originally starting from a generic fragment library, hits progress from 930 µM down to 14 µM within 3 iterations for the fragments selected via in silico molecular interaction energy profiling from a bespoke library. These dinucleotide siRNA guide strand surrogates represent potential new siRNA-based therapeutics (when attached to siRNA to form bioconjugates) featuring improved efficacy, specificity, stability and cellular uptake. This project yielded a portfolio of 7 patent applications, two of which have been granted to date
Dissolution and Translational Modeling Strategies Toward Establishing an In Vitro-In Vivo Link—a Workshop Summary Report
No full textThis publication summarizes the proceedings of day 2 of a 3-day workshop on “Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development.” Patient-centric drug product development from a drug product quality perspective necessitates the establishment of clinically relevant drug product specifications via an in vitro-in vivo link. Modeling and simulation offer a path to establish this link; in this regard, physiologically based modeling has been implemented successfully to support regulatory decision-making and drug product labeling. In this manuscript, case studies of physiologically based biopharmaceutics modeling (PBBM) applied to drug product quality are presented and summarized. These case studies exemplify a possible path to achieve an in vitro-in vivo link and encompass (a) development of biopredictive dissolution methods to support biowaivers, (b) model-informed formulation selection, (c) predicting clinical formulation performance, and (d) defining a safe space for regulatory flexibility via virtual bioequivalence (BE). Workflows for the development and verification of absorption models/PBBM and for the establishment of a safe space using dissolution as an input are described with examples. Breakout session discussions on topics, such as current challenges and some best practices in model development and verification, are included as part of the Supplementary material