14 research outputs found
Integrating the SWAP and Rorschach composite measures for exploring psychopathological patterns of mental functioning
No full textThis study addressed the exploration of a multimethod psychodynamic assessment and its relation to psychopathological patterns. The study applies the Shedler-Westen Assessment Procedure (SWAP; Shedler, J., & Westen, D., 2006, Personality diagnosis with Shedler-Westen Assessment Procedure (SWAP): Bridging the gulf between science and practice. In P. D. M. Task Force (Ed.), Psychodynamic Diagnostic Manual (pp. 573–613). Silver Spring, MD: Alliance of Psychoanalytic Organizations.) and three composite Rorschach measures to a sample of 72 outpatients with various Diagnostic and Statistical Manual of Mental Disorders Axis I diagnoses (American Psychiatric Association, 2000, Diagnostic and Statistical Manual of Mental Disorders (DSM–IV–TR). Washington, DC: Author.): The Ego Impairment Index (EII-2; Viglione, D. J., Perry, W., & Meyer, G. J., 2003, Refinements in the Rorschach Ego Impairment Index incorporating the Human Representational Variable. Journal of Personality Assessment, 81, 149–156. doi:10.1207/S15327752JPA8102_06), measuring maladaptive ego functions; and two derivations of the Reality-Fantasy Scale (RFS; Tibon, S., Handelzalts, J. E., & Weinberger, Y., 2005. Using the Rorschach for exploring the concept of transitional space within the political context of the Middle East. International Journal of Applied Psychoanalytic Studies, 2, 40–57. doi:10.1002/aps.30): the RFS-P, measuring proneness to fantasy (lowered negative scores) as compared to concrete thinking (elevated positive scores); and the RFS-S, measuring dissociative proneness. Consistent with the literature, in this study, the multimethod assessment revealed modest unilinear associations, if any, between each of the Rorschach indices and the SWAP scales. However, regression analyses showed that the joint use of the EII-2 and the RFS-P explained a substantial portion of the variance in the SWAP scales that indicate inhibition and avoidance (obsessive personality disorder score and Avoidant Q factor, respectively). Furthermore, when used with the RFS-S, the EII-2 was able to significantly explain variance in the SWAP scales that indicate interpersonal detachment (schizotypal personality disorder score and Schizoid Q factor). The implications of these results for clinical practice will be discussed
Prodrug Approach to Exploit (S) Alanine as Arginine Mimic Moiety in the Development of Protein Arginine Methyltransferase 4 Inhibitors
No full textProtein arginine methyltransferase (PRMT) 4 (also known as coactivator-associated arginine methyltransferase 1; CARM1) is involved in a variety of biological processes and is considered as an emerging target class in oncology and other diseases. A successful strategy to identify PRMT substrate-competitive inhibitors has been to exploit chemical scaffolds able to mimic the arginine substrate. (S)-Alanine amide moiety is a valuable arginine mimic for the development of potent and selective PRMT4 inhibitors; however, its high hydrophilicity led to derivatives with poor cellular outcomes. Here, we describe the development of PRMT4 inhibitors featuring a central pyrrole core and an alanine amide moiety. Rounds of optimization, aimed to increase lipophilicity and simultaneously preserve the inhibitory activity, produced derivatives that, despite good potency and physicochemical properties, did not achieve on-target effects in cells. On the other hand, masking the amino group with a NAD(P)H:quinone oxidoreductase 1 (NQO1)-responsive trigger group, led to prodrugs able to reduce arginine dimethylation of the PRMT4 substrates BRG1-associated factor 155 (BAF155). These results indicate that prodrug strategies can be successfully applied to alanine-amide containing PRMT4 inhibitors and provide an option to enable such compounds to achieve sufficiently high exposures in vivo
Exploring the Anticancer Potential of Premna resinosa (Hochst.) Leaf Surface Extract: Discovering New Diterpenes as Heat Shock Protein 70 (Hsp70) Binding Agents
No full textPremna, a genus consisting of approximately 200 species, predominantly thrives in tropical and subtropical areas. Many of these species have been utilized in ethnopharmacology for diverse medicinal applications. In Saudi Arabia, Premna resinosa (Hochst.) Schauer (Lamiaceae) grows wildly, and its slightly viscid leaves are attributed to the production of leaf accession. In this study, we aimed to extract the surface accession from fresh leaves using dichloromethane to evaluate the anticancer potential. The plant exudate yielded two previously unknown labdane diterpenes, Premnaresone A and B, in addition to three already described congeners and four known flavonoids. The isolation process was accomplished using a combination of silica gel column chromatography and semi preparative HPLC, the structures of which were identified by NMR and HRESIMS analyses and a comparison with the literature data of associated compounds. Furthermore, we employed a density functional theory (DFT)/NMR approach to suggest the relative configuration of different compounds. Consequently, we investigated the possibility of developing new chaperone inhibitors by subjecting diterpenes 1–5 to a Surface Plasmon Resonance-screening, based on the knowledge that oridonin, a diterpene, interacts with Heat Shock Protein 70 (Hsp70) 1A in cancer cells. Additionally, we studied the anti-proliferative activity of compounds 1–5 on human Jurkat (human T-cell lymphoma) and HeLa (epithelial carcinoma) cell lines, where diterpene 3 exhibited activity in Jurkat cell lines after 48 h, with an IC50 of 15.21 ± 1.0 μM. Molecular docking and dynamic simulations revealed a robust interaction between compound 3 and Hsp70 key residues
quinoxaline-based compounds targeting the bromodomain of BRD9
No full textHere we report a detailed structure-activity relationship (SAR) study related to [1,2,4]triazolo[4,3-a]quinoxaline-based compounds targeting the reader module of bromodomain containing-protein 9 (BRD9). 3D structurebased pharmacophore models, previously introduced by us, were here employed to evaluate a second generation of compounds, exploring different substitution patterns on the heterocyclic core. Starting from the promising data obtained from our previously identified [1,2,4]triazolo[4,3-a]quinoxaline-based compounds 1-4, the combination of in silico studies, chemical synthesis, biophysical and in vitro assays led to the identification of a new set of derivatives, selected for thoroughly exploring the chemical space of the bromodomain binding site. In more details, the investigation of different linkers at C-4 position highlighted the amine spacer as mandatory for the binding with the protein counterpart and the crucial role of the alkyl substituents at C-1 for increasing the selectivity toward BRD9. Additionally, the importance of a hydrogen bond donor group, critical to anchor the ZA region and required for the interaction with Ile53 residue, was inferred from the analysis of our collected results. Herein we also propose an optimization and an update of our previously reported "pharm-druglike2" 3D structure-based pharmacophore model, introducing it as "pharm-druglike2.1". Compounds 24-26, 32, 34 and 36 were identified as new valuable BRD9 binders featuring IC50 values in the low micromolar range. Among them, 24 and 36 displayed an excellent selectivity towards BRD9 and a good antiproliferative effect on a panel of leukemia models, especially toward CCRF-CEM cell line, with no cytotoxicity on healthy cells. Notably, the interaction of 24 and 36 with the bromodomain and PHD finger-containing protein 1 (BRPF1) also emerged, disclosing them as new and unexplored dual inhibitors for these two proteins highly involved in leukemia. These findings highlight the potential for the identification of new attractive dual epidrugs as well as a promising starting point for the development of chemical degraders endowed with anticancer activities
Repositioning of Quinazolinedione-Based Compounds on Soluble Epoxide Hydrolase (sEH) through 3D Structure-Based Pharmacophore Model-Driven Investigation
No full textThe development of new bioactive compounds represents one of the main purposes of the drug discovery process. Various tools can be employed to identify new drug candidates against pharmacologically relevant biological targets, and the search for new approaches and methodologies often represents a critical issue. In this context, in silico drug repositioning procedures are required even more in order to re-evaluate compounds that already showed poor biological results against a specific biological target. 3D structure-based pharmacophoric models, usually built for specific targets to accelerate the identification of new promising compounds, can be employed for drug repositioning campaigns as well. In this work, an in-house library of 190 synthesized compounds was re-evaluated using a 3D structure-based pharmacophoric model developed on soluble epoxide hydrolase (sEH). Among the analyzed compounds, a small set of quinazolinedione-based molecules, originally selected from a virtual combinatorial library and showing poor results when preliminarily investigated against heat shock protein 90 (Hsp90), was successfully repositioned against sEH, accounting the related built 3D structure-based pharmacophoric model. The promising results here obtained highlight the reliability of this computational workflow for accelerating the drug discovery/repositioning processes
Identification of 2,4,5-trisubstituted-2,4-dihydro-3H-1,2,4-triazol-3-one-based small molecules as selective BRD9 binders
No full text: Targeting bromodomain-containing protein 9 (BRD9) represents a promising strategy for the development of new agents endowed with anticancer properties. With this aim, a set of 2,4,5-trisubstituted-2,4-dihydro-3H-1,2,4-triazol-3-one-based compounds was investigated following a combined approach that relied on in silico studies, chemical synthesis, biophysical and biological evaluation of the most promising items. The protocol was initially based on molecular docking experiments, accounting a library of 1896 potentially synthesizable items tested in silico against the bromodomain of BRD9. A first set of 21 compounds (1-21) was selected and the binding on BDR9 was assessed through AlphaScreen assays. The obtained results disclosed compounds 17 and 20 able to bind BRD9 in the submicromolar range (IC50 = 0.35 ± 0.18 μM and IC50 = 0.14 ± 0.03 μM, respectively) showing a promising selectivity profile when tested against further nine bromodomains. Taking advantage of 3D structure-based pharmacophore models, additional 10 derivatives were selected in silico for the synthetic step and binding assessment, highlighting seven compounds (22, 23, 25, 26, 28, 29, 31) able to selectively bind BRD9 among different bromodomains. The ability of the identified BRD9 binders to cross artificial membranes in vitro was also assessed, revealing a very good passive permeability profile. Preliminary studies were carried out on a panel of healthy and cancer human cell lines to explore the biological behavior of the selected compounds, disclosing a moderate activity and significant selectivity profile towards leukaemia cells. These results highlighted the applicability of the reported multidisciplinary approach for accelerating the selection of promising items and for driving the chemical synthesis of novel selective BRD9 binders. Moreover, the low molecular weight of the reported 2,4,5-trisubstituted-2,4-dihydro-3H-1,2,4-triazol-3-one-based BRD9 binders suggests the possibility for further exploring the chemical space in order to obtain new analogues with improved potency
Fatty Acid Synthase as Interacting Anticancer Target of the Terpenoid Myrianthic Acid Disclosed by MS-Based Proteomics Approaches
No full textThis research focuses on the target deconvolution of the natural compound myrianthic acid, a triterpenoid characterized by an ursane skeleton isolated from the roots of Myrianthus arboreus and from Oenothera maritima Nutt. (Onagraceae), using MS-based chemical proteomic techniques. Application of drug affinity responsive target stability (DARTS) and targeted-limited proteolysis coupled to mass spectrometry (t-LiP-MS) led to the identification of the enzyme fatty acid synthase (FAS) as an interesting macromolecular counterpart of myrianthic acid. This result, confirmed by comparison with the natural ursolic acid, was thoroughly investigated and validated in silico by molecular docking, which gave a precise picture of the interactions in the MA/FAS complex. Moreover, biological assays showcased the inhibitory activity of myrianthic acid against the FAS enzyme, most likely related to its antiproliferative activity towards tumor cells. Given the significance of FAS in specific pathologies, especially cancer, the myrianthic acid structural moieties could serve as a promising reference point to start the potential development of innovative approaches in therapy
Unveiling New Triazoloquinoxaline‐Based PROTACs Designed for the Selective Degradation of the ncBAF Chromatin Remodeling Subunit BRD9
No full textPROteolysis Targeting Chimera (PROTAC) technology is an innovative and potent approach for achieving targeted protein degradation (TPD). Within bromodomain-containing proteins, various degraders targeting BET family-related targets, for example, BRD4, were developed in the last years. On the other hand, a limited number of PROTACs acting against non-BET proteins were reported so far. Among them, BRD9 was recently linked to oncogenic roles in the tumorigenesis processes, especially in sarcomas and leukemias. Herein, we describe the design and synthesis of a focused collection of new BRD9-targeting degraders based on the [1,2,4]triazolo[4,3-a]quinoxaline heterocyclic scaffold employing two distinct E3 ubiquitin ligase ligands. Through in silico evaluation, synthesis, binding affinity determination, and in vitro analysis, we identified two new VHL-based PROTACs (2 and 9), which showed remarkable degradation of the protein of interest and antiproliferative activity in acute myeloid leukemia (AML) cells. Notably, compound 9 exhibited selective degradation of BRD9 over BRD7. These results enlarge and differentiate the pool of heterobifunctional molecules able to degrade BRD9 through the proteasome machinery, providing a promising reference for the discovery of new tools to further explore both the involvement of this epigenetic regulatory factor in tumor processes and to evaluate novel strategies for AML treatment
Case formulation of interpersonal patterns and its impact on the therapeutic process: Introduction to the issue
No full textAuthors included in this issue of the Journal of Clinical Psychology: In-Session come from diverse theoretical orientations but discuss methods of case conceptualization that share these assumptions: (1) that interpersonal patterns are salient to a good understanding of patient personality and problems and (2) that an individual formulation is helpful in responsively tailoring in-session processes to meet therapeutic goals. We believe these assumptions resonate with many practitioners working across settings, levels of severity, and theoretical orientations. Each author offers an overview of theory as well as a detailed case description that emphasizes the implications of each formulation for the subsequent process of therapy. A final paper provides commentary across the source papers. The issue is thus evocative not only about clinical practice issues but also of underlying theory. It speaks to the challenges and possibilities of transtheoretical integrated practice and research within our focal domain of common interest, interpersonal relationships
A Comprehensive In Vitro Characterization of a New Class of Indole-Based Compounds Developed as Selective Haspin Inhibitors
No full textHaspin is an emerging, but rather unexplored, divergent kinase involved in tumor growth by regulating the mitotic phase. In this paper, the in-silico design, synthesis, and biological characterization of a new series of substituted indoles acting as potent Haspin inhibitors are reported. The synthesized derivatives have been evaluated by FRET analysis, showing very potent Haspin inhibition. Then, a comprehensive in-cell investigation highlighted compounds 47 and 60 as the most promising inhibitors. These compounds were challenged for their synergic activity with paclitaxel in 2D and 3D cellular models, demonstrating a twofold improvement of the paclitaxel antitumor activity. Compound 60 also showed remarkable selectivity when tested in a panel of 70 diverse kinases. Finally, in-silico studies provided new insight about the chemical requirements useful to develop new Haspin inhibitors. Biological results, together with the drug-likeness profile of 47 and 60, make these derivatives deserving further studies
