Expanding the inhibitor space of the WWP1 and WWP2 HECT E3 ligases.

The HECT E3 ubiquitin ligases 1 (WWP1) and 2 (WWP2) are responsible for the ubiquitin-mediated degradation of key tumour suppressor proteins and are dysregulated in various cancers and diseases. Here we expand their limited inhibitor space by identification of NSC-217913 displaying a WWP1 IC50 of 158.3 µM (95% CI = 128.7, 195.1 µM). A structure-activity relationship by synthesis approach aided by molecular docking led to compound 11 which displayed increased potency with an IC50 of 32.7 µM (95% CI = 24.6, 44.3 µM) for WWP1 and 269.2 µM (95% CI = 209.4, 347.9 µM) for WWP2. Molecular docking yielded active site-bound poses suggesting that the heterocyclic imidazo[4,5-b]pyrazine scaffold undertakes a π-stacking interaction with the phenolic group of tyrosine, and the ethyl ester enables strong ion-dipole interactions. Given the therapeutic potential of WWP1 and WWP2, we propose that compound 11 may provide a basis for future lead compound development.

Nature should be the model for microbial sciences.

Until recently, microbiologists have relied on cultures to understand the microbial world. As a result, model organisms have been the focus of research into understanding Bacteria and Archaea at a molecular level. Diversity surveys and metagenomic sequencing have revealed that these model species are often present in low abundance in the environment; instead, there are microbial taxa that are cosmopolitan in nature. Due to the numerical dominance of these microorganisms and the size of their habitats, these lineages comprise mind-boggling population sizes upward of 1028 cells on the planet. Many of these dominant groups have cultured representatives and have been shown to be involved in mediating key processes in nature. Given their importance and the increasing need to understand changes due to climate change, we propose that members of Nitrosophaerota (Nitrosopumilus maritimus), SAR11 (Pelagibacter ubique), Hadesarchaeia, Bathyarchaeia, and others become models in the future. Abundance should not be the only measure of a good model system; there are other organisms that are well suited to advance our understanding of ecology and evolution. For example, the most well-studied symbiotic bacteria, like Buchnera, Aliivibrio, and Rhizobium, should be models for understanding host-associations. Also, there are organisms that hold new insights into major transitions in the evolution of life on the planet like the Asgard Archaea (Heimdallarchaeia). Innovations in a variety of in situ techniques have enabled us to circumvent culturing when studying everything from genetics to physiology. Our deepest understanding of microbiology and its impact on the planet will come from studying these microbes in nature. Laboratory-based studies must be grounded in nature, not the other way around.

Development of a High-Sensitivity Millimeter-Wave Radar Imaging System for Non-Destructive Testing.

There is an urgent need to develop non-destructive testing (NDT) methods for infrastructure facilities and residences, etc., where human lives are at stake, to prevent collapse due to aging or natural disasters such as earthquakes before they occur. In such inspections, it is desirable to develop a remote, non-contact, non-destructive inspection method that can inspect cracks as small as 0.1 mm on the surface of a structure and damage inside and on the surface of the structure that cannot be seen by the human eye with high sensitivity, while ensuring the safety of the engineers inspecting the structure. Based on this perspective, we developed a radar module (absolute gain of the transmitting antenna: 13.5 dB; absolute gain of the receiving antenna: 14.5 dB) with very high directivity and minimal loss in the signal transmission path between the radar chip and the array antenna, using our previously developed technology. A single-input, multiple-output (SIMO) synthetic aperture radar (SAR) imaging system was developed using this module. As a result of various performance evaluations using this system, we were able to demonstrate that this system has a performance that fully satisfies the abovementioned indices. First, the SNR in millimeter-wave (MM-wave) imaging was improved by 5.4 dB compared to the previously constructed imaging system using the IWR1443BOOST EVM, even though the measured distance was 2.66 times longer. As a specific example of the results of measurements on infrastructure facilities, the system successfully observed cracks as small as 0.1 mm in concrete materials hidden under glass fiber-reinforced tape and black acrylic paint. In this case, measurements were also made from a distance of about 3 m to meet the remote observation requirements, but the radar module with its high-directivity and high-gain antenna proved to be more sensitive in detecting crack structures than measurements made from a distance of 780 mm. In order to estimate the penetration length of MM waves into concrete, an experiment was conducted to measure the penetration of MM waves through a thin concrete slab with a thickness of 3.7 mm. As a result, Λexp = 6.0 mm was obtained as the attenuation distance of MM waves in the concrete slab used. In addition, transmission measurement experiments using a composite material consisting of ceramic tiles and fireproof board, which is a component of a house, and experiments using composite plywood, which is used as a general housing construction material in Japan, succeeded in making perspective observations of defects in the internal structure, etc., which are invisible to the human eye.

Attribute Feature Perturbation-Based Augmentation of SAR Target Data.

Large-scale, diverse, and high-quality data are the basis and key to achieving a good generalization of target detection and recognition algorithms based on deep learning. However, the existing methods for the intelligent augmentation of synthetic aperture radar (SAR) images are confronted with several issues, including training instability, inferior image quality, lack of physical interpretability, etc. To solve the above problems, this paper proposes a feature-level SAR target-data augmentation method. First, an enhanced capsule neural network (CapsNet) is proposed and employed for feature extraction, decoupling the attribute information of input data. Moreover, an attention mechanism-based attribute decoupling framework is used, which is beneficial for achieving a more effective representation of features. After that, the decoupled attribute feature, including amplitude, elevation angle, azimuth angle, and shape, can be perturbed to increase the diversity of features. On this basis, the augmentation of SAR target images is realized by reconstructing the perturbed features. In contrast to the augmentation methods using random noise as input, the proposed method realizes the mapping from the input of known distribution to the change in unknown distribution. This mapping method reduces the correlation distance between the input signal and the augmented data, therefore diminishing the demand for training data. In addition, we combine pixel loss and perceptual loss in the reconstruction process, which improves the quality of the augmented SAR data. The evaluation of the real and augmented images is conducted using four assessment metrics. The images generated by this method achieve a peak signal-to-noise ratio (PSNR) of 21.6845, radiometric resolution (RL) of 3.7114, and dynamic range (DR) of 24.0654. The experimental results demonstrate the superior performance of the proposed method.

Pyrazolo[1,5-a]pyrimidine as a Prominent Framework for Tropomyosin Receptor Kinase (Trk) Inhibitors-Synthetic Strategies and SAR Insights.

Tropomyosin receptor kinases (Trks) are transmembrane receptor tyrosine kinases named TrkA, TrkB, and TrkC and encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively. These kinases have attracted significant attention and represent a promising therapeutic target for solid tumor treatment due to their vital role in cellular signaling pathways. First-generation TRK inhibitors, i.e., Larotrectinib sulfate and Entrectinib, received clinical approval in 2018 and 2019, respectively. However, the use of these inhibitors was significantly limited because of the development of resistance due to mutations. Fortunately, the second-generation Trk inhibitor Repotrectinib (TPX-0005) was approved by the FDA in November 2023, while Selitrectinib (Loxo-195) has provided an effective solution to this issue. Another macrocycle-based analog, along with many other TRK inhibitors, is currently in clinical trials. Two of the three marketed drugs for NTRK fusion cancers feature a pyrazolo[1,5-a] pyrimidine nucleus, prompting medicinal chemists to develop numerous novel pyrazolopyrimidine-based molecules to enhance clinical applications. This article focuses on a comprehensive review of chronological synthetic developments and the structure-activity relationships (SAR) of pyrazolo[1,5-a]pyrimidine derivatives as Trk inhibitors. This article will also provide comprehensive knowledge and future directions to the researchers working in the field of medicinal chemistry by facilitating the structural modification of pyrazolo [1,5-a]pyrimidine derivatives to synthesize more effective novel chemotherapeutics as TRK inhibitors.

A new ship tracing technology from oil spills based on multi-source data.

Oil spill from ship can cause serious pollution to the Marine environment, but it is very difficult to find and confirm the troublemaker. In order to determine the oil spill ship, this paper proposes a new method to trace the source of ship oil spills and find the suspected ship that spills oil based on SAR imagery, AIS data and related marine environment data. First, we filter AIS data based on position of oil spill areas on remote sensing imagery and convert oil spill areas into trajectory points. Secondly, based on the Lagrangian particle motion model, a bidirectional drift model is proposed to calculate the average similarity between the forward and backward drift results. Finally, the most likely oil spill ship is determined according to the average similarity results. The results of the case study show that the method is effective and practical.

Green Synthetic and Pharmacological Developments in the Hybrid Quinazolinone Moiety: An Updated Review.

Bicyclic quinazolinone constitutes an important class of organic framework enveloping numerous biological properties which enthused organic and medicinal chemists to explore green synthetic strategies for the construction of quinazolinone hybrids with significantly improved pharmacodynamics and pharmacokinetic profiles. In this perspective, the present review summarizes the most recent green synthetic strategies, biological properties, structure-activity relationship, and molecular docking studies of the 4-quinazolinone-based scaffold. This review provides deeper insight into the hit-to-lead synthesis of quinazolinone derivatives in the development of clinically important therapeutic candidates.

Boosting of retinol activity using novel lecithin: Retinol acyltransferase inhibitors.

Lecithin:retinol acyltransferase (LRAT) is the main enzyme catalysing the esterification of retinol to retinyl esters and, hence, is of central importance for retinol homeostasis. As retinol, by its metabolite retinoic acid, stimulates fibroblasts to synthesize collagen fibres and inhibits collagen-degrading enzymes, the inhibition of LRAT presents an intriguing strategy for anti-ageing ingredients by increasing the available retinol in the skin. Here, we synthesized several derivatives mimicking natural lecithin substrates as potential LRAT inhibitors. By exploring various chemical modifications of the core scaffold consisting of a central amino acid and an N-terminal acylsulfone, we explored 10 different compounds in a biochemical assay, resulting in two compounds with IC50 values of 21.1 and 32.7 µM (compounds 1 and 2), along with a simpler arginine derivative with comparative inhibitory potency. Supported by computational methods, we investigated their structure-activity relationship, resulting in the identification of several structural features associated with high inhibition of LRAT. Ultimately, we conducted an ex vivo study with human skin, demonstrating an increase of collagen III associated with a reduction of the skin ageing process. In conclusion, the reported compounds offer a promising approach to boost retinol abundance in human skin and might present a new generation of anti-ageing ingredients for cosmetic application.

La lécithine/rétinol acyltransférase (LRAT) est la principale enzyme qui catalyse l'estérification du rétinol en esters de rétinyle et, par conséquent, est d'une importance centrale pour l'homéostasie du rétinol. Étant donné que le rétinol, par son métabolite l'acide rétinoïque, stimule les fibroblastes pour synthétiser les fibres de collagène et inhibe les enzymes de dégradation du collagène, l'inhibition de la LRAT constitue une stratégie intéressante pour les ingrédients anti­âge en augmentant le rétinol disponible dans la peau. Ici, nous avons synthétisé plusieurs dérivés imitant les substrats naturels de la lécithine comme inhibiteurs de LRAT potentiels. En étudiant différentes modifications chimiques du noyau composé d'un acide aminé central et d'un acylsulfone N­terminal, nous avons étudié dix composés différents dans le cadre d'un essai biochimique; il en est résulté deux composés avec des valeurs de CI50 de 21.1 et 32.7 µm (composés 1 et 2), ainsi qu'un dérivé d'arginine plus simple avec une puissance inhibitrice comparative. Avec le soutien de méthodes computationnelles, nous avons étudié leur relation structure­activité, ce qui a permis d'identifier plusieurs caractéristiques structurelles associées à une inhibition élevée de la LRAT. Enfin, nous avons mené une étude ex vivo sur la peau humaine, démontrant une augmentation du collagène III associée à une réduction du processus de vieillissement de la peau. En conclusion, les composés rapportés offrent une approche prometteuse pour stimuler l'abondance du rétinol dans la peau humaine et pourraient aboutir à une nouvelle génération d'ingrédients anti­âge pour des applications cosmétiques.

Ten years of oil pollution detection in the Eastern Mediterranean shipping lanes opposite the Egyptian coast using remote sensing techniques.

The Eastern Mediterranean region, a vital conduit for global maritime trade, faces significant environmental challenges due to marine pollution, particularly from oil spills. This is the first study covering the long period of comprehensive monitoring of oil pollution using the full mission of Sentinel-1 Synthetic Aperture Radar (SAR) data in the Mediterranean Sea, so this research aims to detect and analyze comprehensively the occurrence of oil spills in the Eastern Mediterranean over a decade (2014-2023). This study focuses on identifying geographical distribution patterns, proximity to shorelines, frequency across maritime zones, and potential sources of these spills, especially around major ports and maritime routes. This study utilizes SAR data from the Sentinel-1 satellite. The methodology included automated detection algorithms within the Sentinel application platform (SNAP) and integration with GIS mapping to study oil spill patterns and characteristics. Over 1000 Sentinel-1 scenes were investigated in the northern Mediterranean waters off the coast of Egypt, to detect and analyze 355 oil spill events with a total impacted area of more than 6000 km2. The analysis of temporal spill distribution reveals significant fluctuations from year to year. Within the entire timeline of the study, 2017 had the largest spatial areas covering one thousand square kilometers. In contrast, the single largest spill recorded during the study period occurred in 2020, covering 198.73 square kilometers. The results identified a non-uniform distribution of oil spills and primarily exhibiting elongated patterns aligned with the navigation routes. The distinct increase of oil spill incidents was within the Exclusive Economic Zone (EEZ), obviously drifted to the coastline and around major ports. The study emphasizes the critical role of remote sensing technologies in addressing environmental challenges caused by the maritime transport sector, advocating for enhanced monitoring and regulatory enforcement to protect marine ecosystems and support sustainable naval activities. The findings highlight the urgent need for targeted continuous monitoring and rapid response strategies in high-traffic maritime areas, particularly around the EEZ and major ports.

Bacterial chemolithoautotrophy in ultramafic plumes along the mid-Atlantic ridge.

Hydrothermal vent systems release reduced chemical compounds that act as an important energy source in the deep sea. Chemolithoautotrophic microbes inhabiting hydrothermal plumes oxidize these compounds, in particular hydrogen and reduced sulfur, to obtain the energy required for CO2 fixation. Here, we analysed the planktonic communities of four hydrothermal systems located along the Mid-Atlantic Ridge: Irinovskoe, Semenov-2, Logatchev-1, and Ashadze-2, by combining long-read 16S rRNA gene analysis, fluorescence in situ hybridization, meta-omics, and thermodynamic calculations. Sulfurimonas and SUP05 dominated the microbial communities in these hydrothermal plumes. Investigation of Sulfurimonas and SUP05 MAGs, and their gene transcription in plumes indicated a niche partitioning driven by hydrogen and sulfur. In addition to sulfur and hydrogen oxidation, a novel SAR202 clade inhabiting the plume, here referred to as genus Carboxydicoccus, harbours the capability for CO-oxidation and CO2 fixation via reverse TCA cycle. Both pathways were also highly transcribed in other hydrogen-rich plumes, including the Von Damm vent field. Carboxydicoccus profundi reached up to 4% relative abundance (1.0 x 103 cell ml- 1) in Irinovskoe non-buoyant plume and was also abundant in non-hydrothermally influenced deep-sea metagenomes (up to 5 RPKM). Therefore, CO, which is probably not sourced from the hydrothermal fluids (1.9-4 µM), but rather from biological activities within the fluid, may serve as a significant energy source in hydrothermal plumes. Taken together, this study sheds light on the chemolithoautotrophic potential of the bacterial community in Mid-Atlantic Ridge plumes.

Advancing drug discovery: Thiadiazole derivatives as multifaceted agents in medicinal chemistry and pharmacology.

In this dispensation of rapid scientific and technological advancements, significant efforts are being made to curb health-related diseases. Research discoveries have highlighted the value of heterocyclic compounds, particularly thiadiazole derivatives, due to their diverse pharmacological activities. These compounds play a crucial role in therapeutic medicine and the development of effective drugs. Thiadiazoles are five-membered heterocyclic compounds consisting of one sulfur and two nitrogen atoms. This review explores advanced synthesis techniques, including the use of heterogeneous catalysts, microwave-assisted methods, ultrasound-assisted synthesis, solvent-free processes, multicomponent reactions, copper-catalyzed aerobic oxidative annulation, intramolecular cyclization, click-chemistry supported synthesis, and alkali-promoted, transition-metal-free mediated synthesis. These methods enhance the diversity and potential applications of thiadiazole compounds. Furthermore, this study provides up-to-date information on the key pharmacological activities of thiadiazole derivatives, highlighting their potential in therapeutic medicine for drug development. The structure-activity relationship (SAR) is also discussed to better understand their interactions and safety in biological systems. This work aims to expand on the reported chemistry and pharmacological potential of the thiadiazole moiety to validate their efficacy as promising pharmacophores in drug design and development.

Evaluation of the nitrosamine impurities of ACE inhibitors using computational, in vitro, and in vivo methods demonstrate no genotoxic potential.

Evaluation and mitigation of the potential carcinogenic risks associated with nitrosamines in marketed pharmaceutical products are areas of interest for pharmaceutical companies and health authorities alike. Significant progress has been made to establish acceptable intake (AI) levels for N-nitrosamine drug substance-related impurities (NDSRIs) using SAR, however some compounds require experimental data to support derivation of a recommended AI. Many angiotensin-converting enzyme inhibitors, identified by the suffix "pril," have secondary amines that can potentially react to form nitrosamines. Here we consider a structural assessment and metabolism data, coupled with comprehensive in vitro and in vivo (mouse) genotoxicity testing to evaluate this particular class of nitrosamines. N-nitroso ramipril and N-nitroso quinapril, both of which are predicted to have inhibited nitrosamine bioactivation due to steric hinderance and branching at the α-position were non-genotoxic in the in vivo liver comet assay and non-mutagenic in the in vivo Big Blue® mutation and duplex sequencing assays. Predicted metabolism along with in vitro metabolism data and quantum chemical calculations related to DNA interactions offer a molecular basis for the negative results observed in both in vitro and in vivo testing. These nitrosamines are concluded to be non-mutagenic and non-carcinogenic; therefore, they should be controlled according to ICH Q3B guidance. Furthermore, these results for N-nitroso ramipril and N-nitroso quinapril should be considered when evaluating the appropriate AI and control strategy for other structurally similar "pril" NDSRIs.

Crystal structure of dihydroneopterin aldolase from Mycobacterium tuberculosis associated with 8-mercaptoguanine, and development of novel S8-functionalized analogues as inhibitors: Synthesis, enzyme inhibition, in vitro toxicity and antitubercular activity.

The crystallographic structure of the FolB enzyme from Mycobacterium tuberculosis (MtFolB), complexed with its inhibitor 8-mercaptoguanine (8-MG), was elucidated at a resolution of 1.95 Å. A novel series of S8-functionalized 8-MG derivatives were synthesised and evaluated as in vitro inhibitors of dihydroneopterin aldolase (DHNA, EC 4.1.2.25) activity of MtFolB. These compounds exhibited IC50 values in the submicromolar range. Evaluation of the activity for five compounds indicated their inhibition mode and inhibition constants. Molecular docking analyses were performed to determine the enzyme-inhibitor intermolecular interactions and ligand conformations upon complex formation. The inhibitory activities of all compounds against the M. tuberculosis H37Rv strain were evaluated. Compound 3e exhibited a minimum inhibitory concentration in the micromolar range. Finally, Compound 3e showed no apparent toxicity in both HepG2 and Vero cells. The findings presented herein will advance the quest for novel, specific inhibitors targeting MtFolB, an attractive molecular target for TB drug development.

Advancements in targeting tumor suppressor genes (p53 and BRCA 1/2) in breast cancer therapy.

Globally, among numerous cancer subtypes, breast cancer (BC) is one of the most prevalent forms of cancer affecting the female population. A female's family history significantly increases her risk of developing breast cancer. BC is caused by aberrant breast cells that proliferate and develop into tumors. It is estimated that 5-10% of breast carcinomas are inherited and involve genetic mutations that ensure the survival and prognosis of breast cancer cells. The most common genetic variations are responsible for hereditary breast cancer but are not limited to p53, BRCA1, and BRCA2. BRCA1 and BRCA2 are involved in genomic recombination, cell cycle monitoring, programmed cell death, and transcriptional regulation. When BRCA1 and 2 genetic variations are present in breast carcinoma, p53 irregularities become more prevalent. Both BRCA1/2 and p53 genes are involved in cell cycle monitoring. The present article discusses the current status of breast cancer research, spotlighting the tumor suppressor genes (BRCA1/2 and p53) along with structural activity relationship studies, FDA-approved drugs, and several therapy modalities for treating BC. Breast cancer drugs, accessible today in the market, have different side effects including anemia, pneumonitis, nausea, lethargy, and vomiting. Thus, the development of novel p53 and BRCA1/2 inhibitors with minimal possible side effects is crucial. We have covered compounds that have been examined subsequently (2020 onwards) in this overview which may be utilized as lead compounds. Further, we have covered mechanistic pathways to showcase the critical druggable targets and clinical and post-clinical drugs targeting them for their utility in BC.

Development and Evaluation of Bis-benzothiazoles as a New Class of Benzothiazoles Targeting DprE1 as Antitubercular Agents.

Benzothiazole-bearing compounds have emerged as potential noncovalent DprE1 (decaprenylphosphoryl-ß-d-ribose-2'-epimerase) inhibitors active against Mycobacterium tuberculosis. Based on structure-based virtual screening (PDB ID: 4KW5), a focused library of thirty-one skeletally diverse benzothiazole amides was prepared, and the compounds were assessed for their antitubercular activity against M.tb H37Ra. Most potent compounds 3b and 3n were further evaluated against the M.tb H37Rv strain by the microdilution assay method. Among the compounds evaluated, bis-benzothiazole amide 3n emerged as a hit molecule and demonstrated promising antitubercular activity with minimum inhibitory concentration (MIC) values of 0.45 µg/mL and 8.0 µg/mL against H37Ra and H37Rv, respectively. Based on the preliminary hit molecule (3n), a focused library of 12 more bis-benzothiazole amide derivatives was further prepared by varying the substituents on either side to obtain new leads and generate a structure-activity relationship (SAR). Among these compounds, 6a, 6c, and 6d demonstrated remarkable antitubercular activity with MIC values of 0.5 µg/mL against H37Ra and 1.0, 2.0, and 8.0 µg/mL against H37Rv, respectively. The most active compound, 6a, also displayed significant efficacy against four drug-resistant tuberculosis strains. Compound 6a was assessed for in vitro cytotoxicity against the HepG2 cell line, and it displayed insignificant cytotoxicity. Furthermore, time-kill kinetic studies demonstrated time- and dose-dependent bactericidal activity of this compound. The GFP release assay revealed that compound 6a targets the inhibition of a cell wall component. SNPs in dprE-1 gene assessment revealed that compound 6a binds to tyrosine at position 314 of DprE1 and replaces it with histidine, causing resistance similar to that of standard TCA1. In silico docking studies further suggest that the strong noncovalent interactions of these compounds may lead to the development of potent noncovalent DprE1 inhibitors.

Therapeutic potential of anticancer activity of nitrogen-containing heterocyclic scaffolds as Janus kinase (JAK) inhibitor: Biological activity, selectivity, and structure-activity relationship.

The JAK-STAT signalling pathway is primarily involved in cytokine signalling and induces various factors namely, erythropoietin, thrombopoietin, interferons, interleukins, and granulocyte colony-stimulating factors. These factors tremendously influenced understanding human health and illness, specifically cancer. Inhibiting the JAK/STAT pathway offers enormous therapeutic promises against cancer. Many JAK inhibitors are now being studied due to their efficacy in various cancer treatments. Further, the Nitrogen-heterocyclic (N-heterocyclic) scaffold has always shown to be a powerful tool for designing and discovering synthetic compounds with diverse pharmacological characteristics. The review focuses on several FDA-approved JAK inhibitors and their systematic categorization. The medicinal chemistry perspective is highlighted and classified review on the basis of N-heterocyclic molecules. Several examples of designing strategies of N-heterocyclic rings including pyrrolo-azepine, purine, 1H-pyrazolo[3,4-d]pyrimidine, 1H-pyrrolo[2,3-b]pyridine, pyrazole, thieno[3,2-d] pyrimidine, and, pyrimidine-based derivatives and their structure-activity relationships (SAR) are discussed. Among the various N-heterocyclic-based JAK inhibitors pyrimidine-containing compound 1 exhibited excellent inhibition activity against JAK2WT and mutated-JAK2V617F with IC50 of 2.01 and 18.84 nM respectively. Amino pyrimidine-containing compound 6 and thiopheno[3,2-d]pyrimidine-containing compound 13 expressed admirable JAK3 inhibition activity with IC50 of 1.7 nM and 1.38 nM respectively. Our review will support the medicinal chemists in refining and directing the development of novel N-heterocyclic-based JAK inhibitors.

Pharmacokinetics, pharmacodynamics, safety, and tolerability of a single-dose riliprubart, an anti-C1s humanized monoclonal antibody in East-Asian adults: results from a Phase 1, randomized, open-label trial.

OBJECTIVES: This Phase 1 trial was planned to investigate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of a single dose of riliprubart in healthy East-Asian adult participants. METHODS: A single-center, parallel-group, randomized, open-label, single-dose study was performed to evaluate the PK, PD, safety, and tolerability of riliprubart (50 mg/kg intravenous [IV] or 600 mg subcutaneous [SC]) in 37 healthy East-Asian (Chinese, Japanese, and Korean) participants. RESULTS: Riliprubart was slowly absorbed after SC administration (median tmax: 7.01-10.48 days) and showed a long half-life after IV or SC administration (mean: 9.52-11.0 weeks), with a bioavailability of 74.6% after SC administration. The PD profiles, which are evaluated by classical complement pathway activity or CH50, were similar and largely overlapped across East-Asian participants after a single IV or SC dose. Riliprubart was safe and well tolerated in participants following a single IV or SC dose. CONCLUSIONS: Riliprubart was safe and well tolerated and demonstrated favorable PK and PD profiles in healthy East-Asian participants following a single IV or SC dose. These results are comparable to first-in-human study results from non-East-Asian participants and support the same dosing regimen of riliprubart for global simultaneous clinical development. CLINICAL TRIAL REGISTRATION: This trial is registered at https://cris.nih.go.kr (identifier: KCT0006571).

Repurposing of CDK Inhibitors as Host Targeting Antivirals: A Mini-Review.

Most of the antiviral drugs in the market are designed to target viral proteins directly. They are generally considered safe for human use. However, they also suffer from several inherent limitations, in particular, narrow-spectrum antiviral profiles and liability to drug resistance. The other strategy for antiviral drug development is targeting host factors, which are highly involved at different stages in the viral life cycle. In contrast to direct-acting antiviral agents, host-targeting antiviral ones normally exhibit broad-spectrum antiviral properties along with a much higher genetic barrier to drug resistance. Cyclin-dependent kinases (CDKs) represent one such host factor. In this review, we summarized a number of CDK inhibitors (CDKIs) of varied chemical scaffolds with demonstrated antiviral activity. Challenges and issues associated with the repurposing of CDKIs as antiviral agents were also discussed.

A Promising Paradigm Shift in Cancer Treatment with FGFR Inhibitors.

FGFR have been demonstrated to perform a crucial role in biological processes but their overexpression has been perceived as the operator component in the occurrence and progression of different types of carcinoma. Out of all the interest around cancer, FGFR inhibitors have assembled pace over the past few years. Therefore, FGFR inhibitors are one of the main fundamental tools to reverse drug resistance, tumor growth, and angiogenesis. Currently, many FGFR inhibitors are under the development stage or have been developed. Due to great demand and hotspots, different pharmacophores were approached to access structurally diverse FGFR inhibitors. Here, we have selected to present several representative examples such as Naphthyl, Pyrimidine, Pyridazine, Indole, and Quinoline derivatives that illustrate the diversity and advances of FGFR inhibitors in medicinal chemistry. This review focuses on the SAR study of FGFR inhibitors last five years which will be a great future scope that influences the medicinal chemist to work towards more achievements in this area.

Discovery of novel amide derivatives against VEGFR-2/tubulin with potent antitumor and antiangiogenic activity.

Dual-target agents have more advantages than drug combinations for cancer treatment. Here, we designed and synthesized a series of novel VEGFR-2/tubulin dual-target inhibitors through a molecular hybridization strategy, and the activities of all the synthesized compounds were tested against tubulin and VEGFR-2. Among which, compound 19 exhibited strong potency against tubulin and VEGFR-2, with IC50 values of 0.76 ± 0.11 µM and 15.33 ± 2.12 nM, respectively. Additionally, compound 19 not only had significant antiproliferative effects on a series of human cancer cell lines, especially MGC-803 cells (IC50 = 0.005 ± 0.001 µM) but also overcame drug resistance in Taxol-resistant MGC-803 cells, with an RI of 1.8. Further studies showed that compound 19 could induce tumor cell apoptosis by reducing the mitochondrial membrane potential, increasing the level of ROS, facilitating the induction of G2/M phase arrest, and inhibiting the migration and invasion of tumor cells in a dose-dependent manner. In addition, compound 19 also exhibits potent antiangiogenic effects by blocking the VEGFR-2/PI3K/AKT pathway and inhibiting the tubule formation, invasion, and migration of HUVECs. More importantly, compound 19 demonstrated favorable pharmacokinetic profiles, robust in vivo antitumor efficacy, and satisfactory safety profiles. Overall, compound 19 can be used as a lead compound for the development of tubulin/VEGFR-2 dual-target inhibitors.