Development Of Inhibitors Research Articles

Discovery of a new lead molecule to develop a novel class of human factor XIIa inhibitors.

Factor XIIa (FXIIa) is a plasma serine protease within the contact activation pathway. Inhibiting FXIIa could offer a viable therapeutic approach for achieving effective and safer anticoagulation without the bleeding risks that accompany the use of existing anticoagulants. Therefore, we investigated the anticoagulant properties of an amidine-containing molecule (inhibitor 1) to identify a potential lead molecule for subsequent development of FXIIa inhibitors. Results indicated that inhibitor 1 primarily inhibits human FXIIa with an IC50 value of ~30 µM. The inhibitor demonstrated variable selectivity against thrombin, factor IXa, factor Xa, factor XIa, and activated protein C. Michaelis-Menten kinetics indicated that the molecule is an active site inhibitor of FXIIa. Molecular modeling studies revealed that the molecule recognizes residues His57, Asp189, and Ala190 in FXIIa's active site. The inhibitor selectively and concentration-dependently prolonged the clotting time of human plasma under activated partial thromboplastin time assay conditions. The inhibitor did not exhibit significant cytotoxicity in human HEK293 cells and the in silico pharmacokinetics and toxicology data were comparable to known anticoagulants. This study introduces inhibitor 1 as a lead platform for further development as an anticoagulant to provide a more effective and safer approach to preventing and treating thromboembolic diseases.

Influence of Cataract Causing Mutations on αA-Crystallin: A Computational Approach.

The αA-crystallin protein plays a vital role in maintaining the refractive index and transparency of the eye lens. Significant clinical studies have emerged as the αA-crystallin is prone to aggregation, resulting in the formation of cataracts with varied etiologies due to mutations. This work aims to comprehend the structural and functional role of cataract-causing mutations in αA-crystallin, particularly at N-Terminal and α-Crystallin Domains, using in-silico approaches including molecular dynamics simulation. About 19 mutants of αA-crystallin along with native structure were simulated for 100 ns and the post-simulations analyses reveal pronounced dynamics of αA-crystallin due to the enhanced structure flexibility as its native compactness was lost and is witnessed mainly by the mutants R12L, R21L, R21Q, R54L, R65Q, R116C and R116H. It is observed that αA-crystallin discloses the NTD motions as the dominant one and the same was endorsed by the linear variation between Rg and the center-of-mass of αA-crystallin. Interestingly, such enhanced dynamics of αA-crystallin mutants associated with the structure flexibility is internally modulated by the dynamic exchange of secondary structure elements β-sheets and coils (R2 = 0.619) during simulation. Besides, the observed pronounced dynamics of dimer interface region (β3-L6-β4 segment) of ACD along with CTD dynamics also gains importance. Particularly, the highly dynamic mutants are also characterized by enhanced non-covalent and hydrophobic interactions which renders detrimental effects towards its stability, and favours possible protein unfolding mechanisms. Overall, this study highlights the mutation-mediated structural distortions in αA-crystallin and demands the need for further potential development of inhibitors against cataract formation.

Structure-guided design and photochemical synthesis of new carbamo(dithioperoxo)thioates with improved potencies to SARS-CoV-2 3CLpro

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has triggered a protracted global pandemic from 2019 to 2022, and posed a significant threat to human health. One of the non-structural proteins 3CLpro of SARS-CoV-2 is considered as a validated target for the development of inhibitors against the virus. Disulfiram has been reported as a covalent inhibitor of 3CLpro; however, its structure lacks bonding site with active pockets of 3CLpro and its highly symmetric structure doesn’t match well with the irregular cavity of the active center, limiting its therapeutic applications. To enhance their affinity for the 3CLpro target, in this study, two kinds of disulfiram derivatives, designed based on the reevaluation and optimization of disulfiram, have been synthesized through photoredox chemistry, and the novel carbamo(dithioperoxo)thioates 4g-m were found to display 5–17 folds potency against SARS-CoV-2 3CLpro compared to the parent disulfiram, with resulting half-maximal inhibitory concentration (IC50) values ranging from 0.14–0.47 μM. Carbamo(dithioperoxo)thioates 4i containing a 4-hydroxy piperidine and a 4-trifluoromethyl phenyl ring, was identified as the most potent inhibitor (IC50 = 0.14 μM). Furthermore, molecular dynamics simulations, binding free energy analysis and mass analysis were performed and provided insights on the stability, conformational behavior, and interactions of 4g with 3CLpro. The green synthetic methodology, the privileged carbamo(dithioperoxo)thioate scaffold, and the molecular mechanisms presented might serve as a useful system for the further discovery of highly potent inhibitors targeting SARS-CoV-2 3CLpro.

STK33 as the functional substrate of miR-454-3p for suppression and apoptosis in neuroblastoma

miR-454-3p has been reported to be a tumor suppressive micro-RNA (miRNA) in multiple cancer types. We identified the kinase STK33 mRNA, which is a high-risk factor for survival in neuroblastoma (NB) patients, as being a substrate of miR-454-3p in NB. Even though STK33 is an attractive target for several cancers, development of inhibitors of STK33 has been challenging. For the various cell lines tested, we demonstrated reduced growth and viability with the miR-454-3p mimic. From among the candidate NB-associated miRNAs, miR-454-3p mimic and its antagonist had the most profound effect on STK33 mRNA and protein level changes. Under various conditions of growth and external stress for the cells, the RNA levels for miR-454-3p and STK33 also negatively correlated. Luciferase reporter assays demonstrated STK33 as a substrate for miR-454-3p, and recombinant versions of STK33 resistant to miR-454-3p significantly blunted the suppressive effect of the miR-454-3p and established STK33 as the major functional substrate of miR-454-3p. Overexpression of miR-454-3p or knockdown of STK33 mRNA promoted autophagy, and at the same time, increased the apoptotic markers in the tested NB cells, indicating a mechanism for the suppressive effect of the agents. Given the difficult-to-drug targets such as STK33 and the recent successes in RNA delivery methods for cancer treatment, it is thought that targeting cancer cells with a suppressive miRNA such as miR-454-3p for STK33-dependent cancer types may be an alternative means of NB therapy.

Probing the Molecular Basis of Aminoacyl-Adenylate Affinity With Mycobacterium tuberculosis Leucyl-tRNA Synthetase Employing Molecular Dynamics, Umbrella Sampling Simulations and Site-Directed Mutagenesis.

Leucyl-tRNA synthetase (LeuRS) is clinically validated molecular target for antibiotic development. Recently, we have reported several classes of small-molecular inhibitors targeting aminoacyl-adenylate binding site of Mycobacterium tuberculosis LeuRS with antibacterial activity. In this work, we performed in silico site-directed mutagenesis of M. tuberculosis LeuRS synthetic site in order to identify the most critical amino acid residues for the interaction with substrate and prove binding modes of inhibitors. We carried out 20-ns molecular dynamics (MD) simulations and used umbrella sampling (US) method for the calculation of the binding free energy (ΔGb) of leucyl-adenylate with wild-type and mutated forms of LeuRS. According to molecular modeling results, it was found that His89, Tyr93, and Glu660 are essential amino acid residues both for aminoacyl-adenylate affinity and hydrogen bond formation. We have selected His89 for experimental site-directed mutagenesis since according to our previous molecular docking results this amino acid residue was predicted to be important for inhibitor interaction in adenine-binding region. We obtained recombinant mutant M. tuberculosis LeuRS H89A. Using aminoacylation assay we have found that the mutation of His89 to Ala in the active site of M. tuberculosis LeuRS results in significant decrease of inhibitory activity for compounds belonging to three different chemical classes-3-phenyl-5-(1-phenyl-1H-[1,2,3]triazol-4-yl)-[1,2,4]oxadiazoles, N-benzylidene-N'-thiazol-2-yl-hydrazines, and 1-oxo-1H-isothiochromene-3-carboxylic acid (4-phenyl-thiazol-2-yl)-amide derivatives. Therefore, the interaction with His89 should be taken into account during further M. tuberculosis LeuRS inhibitors development and optimization.

Targeting ferroptosis: a novel therapeutic strategy for the treatment of retinal diseases

Ferroptosis plays a vital role in the progression of various retinal diseases. The analysis of the mechanism of retinal cell ferroptosis has brought new targeted strategies for treating retinal vascular diseases, retinal degeneration and retinal nerve diseases, and is also a major scientific issue in the field of ferroptosis. In this review, we summarized results from currently available in vivo and in vitro studies of multiple eye disease models, clarified the pathological role and molecular mechanism of ferroptosis in retinal diseases, summed up the existing pharmacological agents targeting ferroptosis in retinal diseases as well as highlighting where future research efforts should be directed for the application of ferroptosis targeting agents. This review indicates that ferroptosis of retinal cells is involved in the progression of age-related/inherited macular degeneration, blue light-induced retinal degeneration, glaucoma, diabetic retinopathy, and retinal damage caused by retinal ischemia-reperfusion via multiple molecular mechanisms. Nearly 20 agents or extracts, including iron chelators and transporters, antioxidants, pharmacodynamic elements from traditional Chinese medicine, ferroptosis-related protein inhibitors, and neuroprotective agents, have a remissioning effect on retinal disease in animal models via ferroptosis inhibition. However, just a limited number of agents have received approval or are undergoing clinical trials for conditions such as iron overload-related diseases. The application of most ferroptosis-targeting agents in retinal diseases is still in the preclinical stage, and there are no clinical trials yet. Future research should focus on the development of more potent ferroptosis inhibitors, improved drug properties, and ideally clinical testing related to retinal diseases.

The role of the cGAS-STING pathway in chronic pulmonary inflammatory diseases

The innate immune system plays a vital role in the inflammatory process, serving as a crucial mechanism for the body to respond to infection, cellular stress, and tissue damage. The cGAS-STING signaling pathway is pivotal in the onset and progression of various autoimmune diseases and chronic inflammation. By recognizing cytoplasmic DNA, this pathway initiates and regulates inflammation and antiviral responses within the innate immune system. Consequently, the regulation of the cGAS-STING pathway has become a prominent area of interest in the treatment of many diseases. Chronic inflammatory lung diseases, such as chronic obstructive pulmonary disease (COPD), asthma, and pulmonary fibrosis, are characterized by persistent or recurrent lung inflammation and tissue damage, leading to diminished respiratory function. This paper explores the mechanism of action of the cGAS-STING signaling pathway in these diseases, examines the development of STING inhibitors and nanomaterial applications, and discusses the potential clinical application prospects of targeting the cGAS-STING pathway in chronic inflammatory lung diseases.

Design Principles and Applications of Fluorescent Kinase Inhibitors for Simultaneous Cancer Bioimaging and Therapy

Kinase inhibitors are potent therapeutic agents in cancer treatment, but their effectiveness is frequently restricted by the inability to image the tumor microenvironment. To address this constraint, kinase inhibitor–fluorophore conjugates have emerged as promising theranostic agents, allowing for simultaneous cancer diagnosis and treatment. These conjugates are gaining attention for their ability to visualize malignant tissues and concurrently enhance therapeutic interventions. This review explores the design principles governing the development of multimodal inhibitors, highlighting their potential as platforms for kinase tracking and inhibition via bioimaging. The structural aspects of constructing such theranostic agents are critically analyzed. This work could shed light on this intriguing field and provide adequate impetus for developing novel theranostic compounds based on small molecule inhibitors and fluorophores.

PARP inhibitors in prostate cancer: clinical applications.

Despite recent advancements in the treatment of metastatic castrate-resistant prostate cancer (mCRPC), this disease remains lethal. A novel family of targeted pharmaceuticals known as poly-ADP-ribose polymerase (PARP) inhibitors has been developed to treat mCRPC patients with homologous recombination repair (HRR) gene alterations. The FDA recently approved olaparib and rucaparib for treating mCRPC patients with HRR gene alterations. Ongoing trials are investigating combination therapies involving PARP inhibitors combined with radiation, chemotherapy, immunotherapy, and androgen receptor signaling inhibitors (ARSIs) to improve the effectiveness of PARP inhibitors and broaden the range of patients who can benefit from the treatment. This review provides an overview of the development of PARP inhibitors in prostate cancer and analyzes the mechanisms underlying their resistance.

Immune-related adverse events in small-cell lung cancer patients treated with immune checkpoint inhibitors: a comprehensive analysis from the FDA adverse event reporting system

BackgroundThe discovery and development of immune checkpoint inhibitors (ICIs) have resulted in their application as a novel therapeutic strategy for patients with small-cell lung cancer (SCLC). However, a comprehensive analysis of the potential adverse effects of ICIs in patients with SCLC remains to be conducted.MethodsAdverse event (ADE) reports relating to SCLC patients, submitted to the FDA Adverse Event Reporting System (FAERS) from the first quarter of 2013 to the second quarter of 2022, were extracted for analysis. The extracted data were subsequently screened and analyzed using the reporting odds ratio (ROR) method to assess the AE reports.ResultsA total of 4,522 ADE reports were obtained from patients with SCLC who had received either chemotherapy alone or a combination of ICIs with chemotherapy. The ROR analysis identified a total of 91 immune-related adverse events in SCLC patients associated with the ICIs (SCLC-irAEs).ConclusionThis study revealed that the adverse effects resulting from irAEs in SCLC patients predominantly affected the hematologic and gastrointestinal systems, with the most severe cases potentially leading to fatality.

Structural Analysis of the 20S Proteasome Using Native Mass Spectrometry and Ultraviolet Photodissociation.

Owing to the role of the 20S proteasome in a wide spectrum of pathologies, including neurodegenerative disorders, proteasome-associated autoinflammatory syndromes (PRAAS), and cardiovascular diseases, understanding how its structure and composition contribute to dysfunction is crucial. As a 735 kDa protein assembly, the 20S proteasome facilitates normal cellular proteostasis by degrading oxidized and misfolded proteins. Declined proteasomal activity, which can be attributed to perturbations in the structural integrity of the 20S proteasome, is considered one of the main contributors to multiple proteasome-related diseases. Devising methods to characterize the structures of 20S proteasomes provides necessary insight for the development of drugs and inhibitors that restore proper proteasomal function. Here, native mass spectrometry was combined with multiple dissociation techniques, including ultraviolet photodissociation (UVPD), to identify the protein subunits comprising the 20S proteasome. UVPD, demonstrating an ability to uncover structural features of large (>300 kDa) macromolecular complexes, provided complementary information to conventional collision-based methods. Additionally, variable-temperature electrospray ionization was combined with UV photoactivation to study the influence of solution temperature on the stability of the 20S proteasome.

Exploring the competitive inhibition of α-glucosidase by citrus pectin enzymatic hydrolysate and its mechanism: An integrated experimental and simulation approach

The endo-polygalacturonase D (PgaD) from Aspergillus niger JL15 was recombinantly expressed in Escherichia coli BL21, exhibiting an optimal activity at 55 °C and pH 4.0. Hydrolysis products of citrus pectin by recombinant PgaD included galacturonic acid (GalA), digalacturonic acid (GalA2), trigalacturonic acid (GalA3), and tetragalacturonic acid (GalA4). The hydrolysates exhibited significant antioxidant capacity and dose-dependent competitive inhibition of α-glucosidase. GalA2 and GalA3 acted as competitive inhibitors of α-glucosidase, with inhibition constant of 0.0589 mmol.L−1 and 0.6732 mmol.L−1, respectively. Molecular dynamics (MD) simulations revealed that both GalA2 and GalA3 penetrated the catalytic pocket of α-glucosidase and formed stable hydrogen bonds with key catalytic residues D352 and D215. The binding free energies of GalA2-α-glucosidase and GalA3-α-glucosidase complexes were − 10.3 ± 0.6 kcal·mol−1 and -10.8 ± 0.7 kcal·mol−1, respectively. These findings might offer new ideas for the development of α-glucosidase inhibitors sourced from citrus pectin, as well as enhance utilization of the renewable plant polysaccharide resources.

Dipeptidyl Peptidase-4 Inhibitors: A Systematic Review of Structure-Activity Relationship Studies

Context: Dipeptidyl peptidase 4 (DPP-4) is a serine exopeptidase enzyme that hydrolyzes the amide bond at the N-terminal of peptides. This enzyme converts incretins, such as glucagon-like peptide I and glucose-dependent insulinotropic peptide, into their inactive forms, thereby preventing them from stimulating insulin secretion. Numerous studies have confirmed the role of DPP-4 in the pathophysiology of type 2 diabetes, leading to the development of various DPP-4 inhibitors. In recent years, research on DPP-4 inhibitors has expanded significantly, resulting in the creation of both non-peptidomimetic heterocyclic compounds and peptidomimetic scaffolds. Evidence Acquisition: This systematic review summarizes all recent advances related to DPP-4 inhibitors up to 2024. It begins by outlining the biochemical characteristics of DPP-4 and general pharmacological principles of DPP-4 inhibition, followed by an overview of the latest developments from recent publications. The review provides valuable insights into the pharmacophores necessary for ligand-protein interactions, aimed at understanding the structure-activity relationship of novel DPP-4 inhibitors. Data for this review was collected from sources including ScienceDirect, PubMed, and Scopus. Results: This review highlights various chemical scaffolds that have been explored in the development of novel DPP-4 inhibitors. It emphasizes scaffolds with significant DPP-4 inhibitory activity, including azoles, azines, sulfonamides, and quinolone motifs. The article also details the structure-activity relationships of newly developed analogs, providing a comprehensive overview of recent advancements in this area. Conclusions: Despite moderate progress in the development of novel DPP-4 inhibitors, emerging molecular aspects of DPP-4 intervention show great promise for future therapeutic developments.

Chalcones as potential pepsin inhibitors: Synthesis, characterization, DFT and molecular docking studies

Pepsin, a unique protease activity at acidic environment in the stomach, can cause chronic inflammation in surrounding tissues after becoming hyperactive lead to enlarged tonsils, vocal fold polyps, laryngopharyngeal cancers, and other diseases. Therefore, design and development of new effective pepsin inhibitors becomes significant. In the present work, we synthesized, and characterized thiophene-based chalcones as anti-pepsin agents. The synthesized chalcones exhibited significantly better pepsin inhibition than commercially available drugs omeprazole and pantoprazole. The in-vitro screening revealed that the synthesized compounds exhibited pepsin inhibition in the range of 53.19–91.14 % at 3 × 10−8 M concentration showing promising results controlling elevated pepsin levels. Compound 3p was found the best inhibitor with an IC50 value 1.02 × 10−9 M. Molecular docking studies executed show the decrease in energy of interaction between pepsin and the synthesized compounds 3(a-t) varies from −69.104 to −83.124 kcal/mol and the highest decreased interaction energy with compound 3p. DFT analyses were conducted to gain a deeper understanding of the structural parameters. Energy minimization and quantum chemical parameters computed using Avagadro and ORCA software indicated ΔE values in the range 9.593–10.246 eV as per DFT calculations. The results obtained from the in vitro studies were supported with in silico studies.

Synthesis and evaluation of anticorrosive properties of cationic benzenesulphonamide surfactants on carbon steel under sweet conditions: Empirical and computational investigations

In this study, three cationic surfactants bearing a benzenesulphonamide moiety as corrosion inhibitors (PSA-8, PSA-10, PSA-12) were synthesized using a straightforward two-step process. Their chemical structures were investigated via spectroscopic tools such as 1H and 13C NMR. The surface activity of as-prepared cationic surfactants was examined. To evaluate the effectiveness of these surfactants in the corrosion protection of carbon steel pipelines (C1018-steel) in a CO2-3.5 % NaCl environment, several techniques were used, including electrochemical measurements (potentiodynamic polarization (PDP) and electrochemical impedance spectroscopy (EIS) techniques), surface morphology examinations applying X-ray photoelectron spectroscopy (XPS) analysis, density functional theory (DFT) calculations, and Monte Carlo (MC) simulations. Notably, the corrosion efficiency of the PSA surfactants was compared with previously reported cationic surfactants containing the CN group (i.e., an electron-withdrawing group). The experimental results showed excellent inhibition performance of the PSA surfactants, with inhibition capacities ranging from 92.8 % to 97.0 %. This indicates that removing the CN group has significantly enhanced the corrosion inhibition efficiency, shedding light on the electronic effectas well as the adsorption and corrosion processes. Analysis of the Tafel data indicated that these surfactants functioned as mixed-type inhibitors and followed the Langmuir isotherm model in their adsorption on the carbon steel interface and the corrosive medium. XPS analysis confirmed the establishment of a shielding barrier at the interface of the carbon steel. DFT calculations were employed to establish the correlations between theoretical parameters and experimental observations, thereby validating their connection. Moreover, the employment of MC simulations validated the efficacy of the adsorption properties of the synthesized surfactants on the iron (110) surface. Ultimately, this investigation provides substantial insights into the development and formulation of bioactive inhibitors characterized by their potent inhibitory effectiveness.

Previously Published Phosphatase Probes have Limited Utility Due to their Unspecific Reactivity.

This study explores the use of activity-based protein profiling to study protein tyrosine phosphatases. With the discovery of allosteric SHP2 inhibitors, this enzyme family has resurfaced as interesting drug targets. Therefore, we envisioned that previously described direct electrophiles and quinone methide-based traps targeting phosphatases could be applied in competitive activity-based protein profiling assays. This study evaluates three direct electrophiles, specifically, a vinyl sulfonate, a vinyl sulfone, and an α-bromobenzylphosphonate as well as three quinone methide-based traps as activity-based probes. For all these moieties it was previously shown that they could selectively engage in assays with purified or overexpressed phosphatases in bacterial lysates. However, this study demonstrates that probes based on these moieties all suffer from unspecific labelling. Direct electrophiles were either unspecific or not activity-based, while quinone methide-based traps showed dependence on phosphatase activity but also resulted in unspecific labelling due to diffusion after activation. This phenomenon, termed 'bystander' labelling, occurred even with catalytically inactive SHP2 mutants. We concluded that alternative strategies or chemistries are needed to apply activity-based protein profiling in phosphatase research. Moreover, this study shows that quinone methide-based designs have limited potential in probe and inhibitor development strategies due to their intrinsic reactivity.

A bibliometric and visualization analysis of entosis research from 2007 to 2024

ObjectiveIn 2007, entosis was proposed as a form of programmed cell death, distinct from apoptosis. This process involves a living cell (internalized cell) actively invading a neighboring live cell of the same type (host cell), forming a cell-in-cell structure. Recently, entosis has been increasingly associated with cancer, leading to significant advancements in research. Despite this progress, a comprehensive and unbiased review of the current state of entosis research is lacking. This study aims to evaluate the developments in the field of entosis over the past decade and highlight emerging research trends.Materials and methodsWe performed a literature search for studies published since the introduction of the entosis concept, using the Web of Science Core Collection database. The bibliometric analysis was conducted using VOSviewer, CiteSpace, Microsoft Excel, and the Bibliometrix R package.ResultsA total of 196 articles from 39 countries and 346 institutions were included. Between 2007 and 2024, research on entosis has seen rapid growth, with most publications originating from China and the United States. The United States also leads in total citations, with Memorial Sloan Kettering Cancer Center emerging as the top research institution. Sun Qiang is the most prolific author in this field, while Overholtzer M has the highest number of citations. Current Molecular Medicine has published the most articles related to entosis. Frequently occurring keywords include “entosis,” “cannibalism,” “autophagy,” and “apoptosis.” In recent years, keywords such as “phagocytosis,” “drug resistance,” and “human cancers” have surged, indicating a growing focus on understanding the role of entosis in tumor progression and exploring its potential as a therapeutic target for cancer treatment.ConclusionsThis study provides the first bibliometric analysis of entosis, detailing its evolution over the last decade. It highlights critical areas of interest, including the development of inhibitors targeting entosis and their potential clinical applications. This research aims to guide future investigations and serve as a valuable resource for scholars exploring entosis in cancer biology.

Scaffold Hopping Method for Design and Development of Potential Allosteric AKT Inhibitors.

Targeting AKT is a practical strategy for cancer therapy in many cancer types. Targeted inhibitors of AKT are attractive solutions for inhibiting the interconnected signaling pathways, like PI3K/Akt/mTOR. Allosteric inhibitors are more desirable among different classes of AKT inhibitors as they could be more specific with fewer off-target proteins. In this study, a ligand/structure-based pipeline was developed to design new allosteric AKT inhibitors by employing the core hopping method. Triciribine, a traditional allosteric AKT inhibitor was used as the template, and the FDA-approved kinase inhibitors for cancer treatment were considered as the cores. The allosteric site in the crystal structure of AKT1 was used to screen the designed compounds. The results were further evaluated using molecular docking, ADME/T analysis, molecular dynamics (MD) simulation, and binding free energy calculations. The outcomes introduced 24 newly designed inhibitors, amongst which three compounds C6, C20, and C16 showed remarkable binding affinity to AKT1. While the docking scores for triciribine was around -8.6 kcal/mol, the docking scores of these compounds were about -11 to -13 kcal/mol. The MD results indicated that designed compounds target the essential residues of the PH domain and kinase domain of AKT, such as Trp80, Thr211, Tyr272, Asp274, and Asp292. Scaffold hopping is a tremendous tool for designing novel anti-cancer agents by improving already known and potential drug compounds. The designed compounds are worth to be examined by experimental investigation in vitro and in vivo.

Structural basis of epitope recognition by anti-alpha-synuclein antibodies MJFR14-6-4-2

Alpha-synuclein (α-syn) inclusions in the brain are hallmarks of so-called Lewy body diseases. Lewy bodies contain mainly aggregated α-syn together with some other proteins. Monomeric α-syn lacks a well-defined three-dimensional structure, but it can aggregate into oligomeric and fibrillar amyloid species, which can be detected using specific antibodies. Here we investigate the aggregate specificity of monoclonal MJFR14-6-4-2 antibodies. We conclude that partial masking of epitope in unstructured monomer in combination with a high local concentration of epitopes is the main reason for MJFR14-6-4-2 selectivity towards aggregates. Based on the structural insight, we produced mutant α-syn that when fibrillated is unable to bind MJFR14-6-4-2. Using these fibrils as a tool for seeding cellular α-syn aggregation, provides superior signal/noise ratio for detection of cellular α-syn aggregates by MJFR14-6-4-2. Our data provide a molecular level understanding of specific recognition of toxic amyloid oligomers, which is critical for the development of inhibitors against synucleinopathies.

Update on the treatment of BRAFmut metastatic melanoma and future perspectives

Abstractv‐Raf murine sarcoma viral oncogene homolog B (BRAF) mutations were first identified in melanoma in 2002, leading to increased cell division and proliferation, and resultant tumour growth. The identification and characterisation of BRAF mutations (BRAFmut) led to the development of several highly specific, BRAF‐, then mitogen‐activated kinase enzyme (MEK)‐targeted therapies that have enabled rapid tumour responses and improved treatment outcomes in most patients with metastatic BRAFmut melanoma. The combination of these two drug classes (BRAF inhibitors and MEK inhibitors) has demonstrated improved response rates, progression‐free survival, and overall survival (OS), along with a more tolerable safety profile, compared with BRAF inhibition alone. In parallel, improved knowledge of the immune system has enabled the development of immune checkpoint inhibitors (ICIs), although immune‐related adverse events with ICIs may prove to be problematic in some patients and require careful management. While targeted therapy appears to provide rapid disease control in a relatively high proportion of patients, the development of secondary resistance may limit the overall duration of responses. Acquired resistance, along with primary resistance, has also been reported for ICIs, with a lower overall response rate to that with targeted therapy, although durable responses have been reported in some responding patients. A combination strategy of targeted therapy with ICIs has demonstrated modest increases in efficacy compared with targeted therapy combinations, although data significance varies across studies, there is increased risk of toxicity, and triple combination therapy has not yet received clinical approval in Europe. Thus, there is an ongoing need to establish optimal sequencing of these treatments in patients with advanced BRAFmut melanoma, and this has become the focus of current research. The aim of this narrative review was to provide an update on the treatment of BRAFmut metastatic melanoma, current guideline recommendations, and future clinical perspectives.