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One challenge of the structural design of a fluorescent probe is how to improve the detection performance on trace target analytes in complex samples. Herein a new polymer fluorescent nanoprobe (2DSP-C28) has been synthesized, by adopting a two-dimensional (2D), spiropyran (SP)-based nanosheet structure with hydrophobic long-chain alkanes (C28). Unlike a traditional SP-based small molecule probe, the 2DSP-C28probe can exhibit quantitative-fluorescent and photochromic properties. Under the detection of metal-ions, the nanoprobe in dimethyl sulfoxide aqueous solution is selectively fluorescent-quenched-responsive for Fe-ions (â¼100µM), with a characteristic stoichiometric ratio of <10, a high sensitivity (limit of detection: â¼0.2µM). When the nanoprobe is incorporated into electrospun polyethylene oxide, it can be used for gas detection, and display a color-change with acid-base gas and identify the HF gas. It is expected that this new polymer fluorescent nanoprobe can be promisingly applied for rapidly environmental monitoring on the ion or gas pollution.
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Stimulator of interferon gene (STING) plays critical roles in the cytoplasmic DNA-sensing pathway and in the induction of inflammatory response. Aberrant cytoplasmic DNA accumulation and STING activation are implicated in numerous inflammatory and autoimmune diseases. Here, we reported the discovery of a series of thiazolecarboxamide-based STING inhibitors through a molecular planarity/symmetry disruption strategy. The privileged compound 15b significantly inhibited STING signaling and suppressed immune-inflammatory cytokine levels in both human and murine cells. In vivo experiments demonstrated 15b effectively ameliorated immune-inflammatory cytokines upregulation in MSA-2-stimulated and Trex1-D18N mice. Furthermore, compound 15b exhibited enhanced efficacy in suppressing interferon-stimulated gene 15 (ISG15), a critical positive feedback regulator of STING. Overall, compound 15b deserves further development for the treatment of STING-associated inflammatory and autoimmune diseases.
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BACKGROUND: Whether programmed cell death-1/ligand-1 (PD-1/PD-L1) blockade-based neoadjuvant treatment may benefit locally advanced oncogene-mutant non-small cell lung cancer (NSCLC) patients remains controversial. This retrospective study was designed to observe the efficacy and safety of neoadjuvant PD-1/PD-L1 blockade plus chemotherapy versus chemotherapy and corresponding tyrosine kinase inhibitors (TKIs) in patients with resectable oncogene-positive NSCLC. METHODS: Patients with potential resectable NSCLC harbouring oncogene alterations who had received neoadjuvant treatment were retrospectively recruited, and an oncogene-negative cohort of patients who received neoadjuvant PD-(L)1 blockade-based neoadjuvant treatment was reviewed for comparison during the same period. The primary aim was to observe the treatment efficacy and event-free survival (EFS) of these agents. Safety profile, molecular target, and immunologic factor data, including PD-L1 expression and tumour mutational burden (TMB), were also obtained. RESULTS: A total of 46 patients were recruited. Thirty-one of them harboured oncogene alterations, including EGFR, KRAS, ERBB2, ROS1, MET, RET, ALK, and FGFR3 alterations. Among the oncogene-positive patients, 18 patients received neoadjuvant PD-(L)1 blockade immunotherapy plus chemotherapy (oncogene-positive IO group), 13 patients were treated with neoadjuvant chemotherapy and/or corresponding TKIs or TKIs alone (oncogene-positive chemo/TKIs group), and the other 15 patients were oncogene negative and received neoadjuvant PD-(L)1 blockade plus chemotherapy (oncogene-negative IO group). The pathological complete response (pCR) and major pathological response (MPR) rates were 22.2% (4 of 18) and 44.4% (8 of 18) in the oncogene-positive IO group, 0% (P = 0.120) and 23.1% (3 of 13) (P = 0.276) in the oncogene-positive chemo/TKIs group, and 46.7% (7 of 15) (P = 0.163) and 80.0% (12 of 15) (P = 0.072) in the oncogene-negative IO group, respectively. By the last follow-up, the median EFS time had not reached in the oncogene-positive IO group, and was 29.5 months in the oncogene-positive chemo/TKIs group and 38.4 months in the oncogene-negative IO group. CONCLUSION: Compared with chemotherapy/TKIs treatment, neoadjuvant treatment with PD-(L)1 blockade plus platinum-based chemotherapy was associated with higher pCR/MPR rates in patients with partially resectable oncogene-mutant NSCLC, while the pCR/MPR rates were lower than their oncogene-negative counterparts treated with PD-(L)1 blockade-based treatment. Specifically, oncogene alteration types and other predictors of response to immunotherapy should be taken into account in clinical practice.
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Protocolos de Quimioterapia Combinada Antineoplásica , Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Terapia Neoadjuvante , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Feminino , Masculino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Idoso , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Inibidores de Checkpoint Imunológico/uso terapêutico , Seguimentos , Taxa de Sobrevida , Adulto , Prognóstico , Oncogenes/genética , Inibidores de Proteínas Quinases/uso terapêutico , Mutação , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismoRESUMO
Necroptosis is a form of regulated necrotic cell death and has been confirmed to play pivotal roles in the pathogenesis of multiple autoimmune diseases such as rheumatoid arthritis (RA) and psoriasis. The development of necroptosis inhibitors may offer a promising therapeutic strategy for the treatment of these autoimmune diseases. Herein, starting from the in-house hit compound 1, we systematically performed structural optimization to discover potent necroptosis inhibitors with good pharmacokinetic profiles. The resulting compound 33 was a potent necroptosis inhibitor for both human I2.1 cells (IC50 < 0.2 nM) and murine Hepa1-6 cells (IC50 < 5 nM). Further target identification revealed that compound 33 was an inhibitor of receptor interacting protein kinase 1 (RIPK1) with favorable selectivity. In addition, compound 33 also exhibited favorable pharmacokinetic profiles (T1/2 = 1.32 h, AUC = 1157 ng·h/mL) in Sprague-Dawley rats. Molecular docking and molecular dynamics simulations confirmed that compound 33 could bind to RIPK1 with high affinity. In silico ADMET analysis demonstrated that compound 33 possesses good drug-likeness profiles. Collectively, compound 33 is a promising candidate for antinecroptotic drug discovery.
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Metal halide perovskites (MHPs) have emerged as attractive candidates for producing green hydrogen via photocatalytic pathway. However, the presence of abundant defects and absence of efficient hydrogen evolution reaction (HER) active sites on MHPs seriously limit the solar-to-chemical (STC) conversion efficiency. Herein, to address this issue, we present a bi-functionalization strategy through decorating MHPs with a molecular molybdenum-sulfur-containing co-catalyst precursor. By virtue of the strong chemical interaction between lead and sulfur and the good dispersion of the molecular co-catalyst precursor in the deposition solution, a uniform and intimate decoration of the MHPs surface with lead sulfide (PbS) and amorphous molybdenum sulfide (MoSx) co-catalysts is obtained simultaneously. We show that the PbS co-catalyst can effectively passivate the Pb-related defects on the MHPs surface, thus retarding the charge recombination and promoting the charge transfer efficiency significantly. The amorphous MoSx co-catalyst further promotes the extraction of photogenerated electrons from MHPs and facilitates the HER catalysis. Consequently, drastically enhanced photocatalytic HER activities are obtained on representative MHPs through the synergistic functionalization of PbS and MoSx co-catalysts. A solar-to-chemical (STC) conversion efficiency of ca. 4.63% is achieved on the bi-functionalized FAPbBr3-xIx, which is among the highest values reported for MHPs.
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Resonance-enhanced emission (REE) effect was discovered and lead to a novel dye family of hydrostyryl pyridinium derivatives in our recent work. Herein, the REE effect was employed to design a red and near-infrared dual-state emissive fluorophore family of SW-OH-NO2 derivatives which were easily synthesized by coupling an electron-withdrawing group (W) onto nitro(hydroxyl)styryl (S-OH-NO2 ) through a C=C double bond as π-bridge. The deprotonation of a phenolic hydroxyl group promoted by a nitro group and the electron-withdrawing group (W) on the other side of the π-bridge triggered resonance, resulting in significantly red-shifted emission. All the resultant SW-OH-NO2 compounds showed excellent dual-state emission behavior. Remarkably, hydrostyryl quinolinium (SQ-OH-NO2 ) is one of the smallest NIR emitter molecular skeleton (λem =725â nm, MW<400) and showed dual-state emission characteristics and obvious viscosity-depended fluorescent behaviors. In addition to constructing electron donor-acceptor structures and prolonging π-bridges, the REE effect promises a reliable strategy toward novel fluorophores with small size, long emissive wavelength, and dual-emission characteristics, and importantly, feasible industrial manufactures and applications due to their easy and low-cost synthesis strategy.
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The photocuring technology based on thiol-ene click reaction can be easily applied for copolymerizing or crosslinking the acrylate monomers for ionogels. However, there is still a problem: when the acrylate monomers contain the popular spiropyran as the stimuli-responsive group, it should be concerned about the participation of the active CîC bond from the ring-opened spiropyran during a thiol-ene reaction, which may in turn affect the stimuli-responsiveness of the spiropyran. Up to now, the structure and properties of spiropyran-containing ionogels in this case have still not been well investigated. Therefore, in this work we carefully study a new spiropyran-containing polyurethane ionogel by crosslinking an acrylate-terminated, spiropyran-containing polyurethane prepolymer and a polythiol in ionic liquid through thiol-ene chemistry. It is found for the first time that, during constructing an ionogel, the coexistence of a reversible thiol-ene reaction between the CîC bond from the ring-opened spiropyran and the thiol group can bring about a different reverse photochromic behavior. The proposed mechanism of the abnormal photochromism is analyzed. In addition, it is also observed that the thiol-ene chemistry can incorporate photomechanical and photoconductive properties into the new spiropyran-containing ionogel.
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In recent years, great efforts have been devoted to reducing emissions from mobile sources with the dramatic growth of motor vehicle and nonroad mobile source populations. Compilation of a mobile source emission inventory is conducive to the analysis of pollution emission characteristics and the formulation of emission reduction policies. This study summarizes the latest compilation approaches and data acquisition methods for mobile source emission inventories. For motor vehicles, a high-resolution emission inventory can be developed based on a bottom-up approach with a refined traffic flow model and real-world speed-coupled emission factors. The top-down approach has advantages when dealing with macroscale vehicle emission estimation without substantial traffic flow infrastructure. For nonroad mobile sources, nonroad machinery, inland river ships, locomotives, and civil aviation aircraft, a top-down approach based on fuel consumption or power is adopted. For ocean-going ships, a bottom-up approach based on automatic identification system (AIS) data is adopted. Three typical cases are studied, including emission reduction potential, a cost-benefit model, and marine shipping emission control. Outlooks and suggestions are given on future research directions for emission inventories for mobile sources: building localized emission models and factor databases, improving the dynamic updating capability of emission inventories, establishing a database of emission factors of unconventional pollutants and greenhouse gas from mobile sources, and establishing an urban high temporal-spatial resolution volatile organic compound (VOC) evaporation emission inventory.
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Poluentes Atmosféricos , Compostos Orgânicos Voláteis , Poluentes Atmosféricos/análise , Monitoramento Ambiental/métodos , Emissões de Veículos/análise , Compostos Orgânicos Voláteis/análise , NaviosRESUMO
Three-dimensional (3D) organic-inorganic hybrid perovskites have demonstrated excellent capability in solar fuel production, while the two-dimensional (2D) counterparts are generally considered inferior candidates due to the high exciton binding energy and weak light absorption. Herein, contrary to our common understanding, we find that 2D perovskites can perform photocatalytic H2 production from HI splitting more efficiently than their 3D counterparts. We observed sharp difference between 2D perovskites crystals with organic phenylalkylammonium cations of different lengths and the 3D counterparts in their stabilization behavior in aqueous solution. Moreover, we show that the organic cations length of the 2D perovskites affects the nanostructures, optoelectronic properties, and the charge transfer process significantly, which determines the photocatalytic activity of the 2D perovskites. Among the 2D perovskites under investigation, phenylmethylammonium lead iodide with the shortest organic cations achieved the best solar-to-chemical conversion efficiency of ca. 1.57 %, which is the highest value ever reported for hybrid perovskites.
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The current trend in the miniaturization of electronic devices has driven the investigation into many nanostructured materials. The ferroelectric material barium titanate (BaTiO3) has garnered considerable attention over the past decade owing to its excellent dielectric and ferroelectric properties. This has led to significant progress in synthetic techniques that yield high quality BaTiO3 nanocrystals (NCs) with well-defined morphologies (e.g., nanoparticles, nanorods, nanocubes and nanowires) and controlled crystal phases (e.g., cubic, tetragonal and multi-phase). The ability to produce nanoscale BaTiO3 with controlled properties enables theoretical and experimental studies on the intriguing yet complex dielectric properties of individual BaTiO3 NCs as well as BaTiO3/polymer nanocomposites. Compared with polymer-free individual BaTiO3 NCs, BaTiO3/polymer nanocomposites possess several advantages. The polymeric component enables simple solution processibility, high breakdown strength and light weight for device scalability. The BaTiO3 component enables a high dielectric constant. In this review, we highlight recent advances in the synthesis of high-quality BaTiO3 NCs via a variety of chemical approaches including organometallic, solvothermal/hydrothermal, templating, molten salt, and sol-gel methods. We also summarize the dielectric and ferroelectric properties of individual BaTiO3 NCs and devices based on BaTiO3 NCs via theoretical modeling and experimental piezoresponse force microscopy (PFM) studies. In addition, viable synthetic strategies for novel BaTiO3/polymer nanocomposites and their structure-composition-performance relationship are discussed. Lastly, a perspective on the future direction of nanostructured BaTiO3-based materials is presented.
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Coal combustion is a dominant source of Hg in atmosphere and is believed to be responsible for increases of atmospheric Hg since industrial revolution. In this study, we compared characteristics of different Hg species emitted from combustion of different types of coal in air and oxygen-enriched environment. Total Hg emissions from coal combustion increased significantly with increase of combustion temperature and the majority of emitted Hg existed in the form of Hg0. Total Hg emissions were 8.61 (5.38-16.48) ng/g (average and range) at 500 °C, while increased to 18.65 (6.49-40.38) ng/g at 900 °C. After burning at high temperatures, the higher percentage of reactive Hg species was observed in the flue gases, which was probably caused by promotion of Hg0 oxidation due to the higher flue gas temperature. Compared with air environment, more Hg (3.00-17.96 ng/g higher than air at 900 °C) was remained in ashes, and the percentage of reactive Hg in flue gases increased by 193%-826% at 900 °C under O2/CO2, which is beneficial for reduction of Hg emissions from coal combustion.
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Poluentes Atmosféricos/análise , Carvão Mineral/análise , Gases/análise , Mercúrio/análise , Temperatura Alta , Oxirredução , Oxigênio , Centrais ElétricasRESUMO
Aiming to a better understanding sources contributions and regional sources of fine particles, a total of 273 filter samples (159 of PM2.5 and 114 of PM1.0) were collected per 8â¯h during the winter 2016 at a southwest suburb of Beijing. Chemical compositions, including water soluble ions, organic carbon (OC), and elemental carbon (EC), as well as secondary organic carbon (SOC), were systematically analyzed and estimated. The total ions concentrations (TIC), OC, and SOC of PM2.5 were with the following order: 16:00-24:00â¯>â¯08:00-16:00â¯>â¯00:00-08:00. Since primary OC and EC were mainly attributed to the residential combustion in the night time, their valley values were observed in the daytime (08:00-16:00). However, the highest ratio value of SOC/OC was observed in the daytime. It is because that SOC is easily formed under sunshine and relatively high temperature in the daytime. Positive matrix factorization (PMF), clustering, and potential source contribution function (PSCF) were employed for apportioning sources contributions and speculating potential sources spatial distributions. The average concentrations of each species and the source contributions to each species were calculated based on the data of species concentrations with an 8â¯h period simulated by PMF model. Six likely sources, including secondary inorganic aerosols, coal combustion, industrial and traffic emissions, road dust, soil and construction dust, and biomass burning, were contributed to PM2.5 accounting for 29%, 21%, 17%, 16%, 9%, 8%, respectively. The results of cluster analysis indicated that most of air masses were transported from West and Northwest directions to the sampling location during the observation campaign. Several seriously polluted areas that might affect the air quality of Beijing by long-range transport were identified. Most of air masses were transported from Western and Northwestern China. According to the results of PSCF analysis, Western Shandong, Southern Hebei, Northern Henan, Western Inner Mongolia, Northern Shaanxi, and the whole Shanxi provinces should be the key areas of air pollution control in China. The exposure-response function was used to estimate the health impact associated with PM2.5 pollution. The population affected by PM2.5 during haze episodes reached 0.31 million, the premature death cases associated with PM2.5 reached 2032. These results provided important implication for making environmental policies to improve air quality in China.
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Poluentes Atmosféricos/análise , Monitoramento Ambiental , Material Particulado/análise , Medição de Risco , Aerossóis/análise , Aerossóis/química , Poluentes Atmosféricos/química , Poluição do Ar/análise , Pequim , Carbono/análise , Carvão Mineral/análise , Poeira/análise , Poluição Ambiental/análise , Material Particulado/química , Estações do Ano , Solo , Emissões de Veículos/análiseRESUMO
CONTEXT: Extensive or long-time use of corticosteroids often causes many toxic side-effects. The ion exchange resins and the coating material, Eudragit, can be used in combination to form a new oral delivery system to deliver corticosteroids. OBJECTIVES: The resin microcapsule (DRM) composed by Amberlite 717 and Eudragit S100 was used to target hydrocortisone (HC) to the colon in order to improve its treatment effect on ulcerative colitis (UC) and reduce its toxic side-effects. METHODS: Hydrocortisone sodium succinate (HSS) was sequentially encapsulated in Amberlite 717 and Eudragit S100 to prepare the HSS-loaded resin microcapsule (HSS-DRM). The scanning electron microscopy (SEM) was employed to investigate the morphology and structure of HSS-DRM. The in vitro release and in vivo studies of pharmacokinetics and intestinal drug residues in rat were used to study the colon-targeting of HSS-DRM. The mouse induced by 2,4,6-trinitrobenzenesulfonic acid was used to study the treatment of HSS-DRM on experimental colitis. RESULTS: SEM study showed good morphology and structure of HSS-DRM. In the in vitro release study, > 80% of HSS was released in the colon environment (pH 7.4). The in vivo studies showed good colon-targeting of HSS-DRM (Tmax = 0.97 h, Cmax = 118.28 µg/mL of HSS; Tmax = 2.16 h, Cmax = 64.47 µg/mL of HSS-DRM). Moreover, the HSS-DRM could reduce adverse reactions induced by HSS and had good therapeutic effects on the experimental colitis. CONCLUSIONS: The resin microcapsule system has good colon-targeting and can be used in the development of colon-targeting preparations.
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Anti-Inflamatórios/administração & dosagem , Colite/tratamento farmacológico , Hidrocortisona/análogos & derivados , Microesferas , Resinas Sintéticas/administração & dosagem , Animais , Anti-Inflamatórios/farmacocinética , Cápsulas , Colite/metabolismo , Hidrocortisona/administração & dosagem , Hidrocortisona/farmacocinética , Camundongos , Ácidos Polimetacrílicos/administração & dosagem , Ácidos Polimetacrílicos/farmacocinética , Distribuição Aleatória , Ratos , Resinas Sintéticas/farmacocinética , Resultado do TratamentoRESUMO
Polyhomologation, recently developed by Shea, is a borane-initiated living polymerization of ylides leading to linear polymethylenes (C1 polymerization) with controlled molecular weight, low polydispersity, and well-defined structures. In this Review, the copolyhomologation of different ylides as well as the combination of polyhomologation with controlled/living (nitroxide-mediated, atom transfer radical, reversible addition-fragmentation chain-transfer) and living (ring opening, anionic) polymerizations is discussed.
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Polímeros/química , Boro/química , Nanoestruturas/química , Óxidos de Nitrogênio/química , PolimerizaçãoRESUMO
O3 and PM2.5 were introduced into the newly revised air quality standard system in February 2012, representing a milestone in the history of air pollution control, and China's urban air quality will be evaluated using six factors (SO2, NO2, O3, CO, PM2.5 and PM10) from the beginning of 2013. To achieve the new air quality standard, it is extremely important to have a primary understanding of the current pollution status in various cities. The spatial and temporal variations of the air pollutants were investigated in 26 pilot cities in China from August 2011 to February 2012, just before the new standard was executed. Hourly averaged SO2, NO2 and PM10 were observed in 26 cities, and the pollutants O3, CO and PM2.5 were measured in 15 of the 26 cities. The concentrations of SO2 and CO were much higher in the cities in north China than those in the south. As for O3 and NO2, however, there was no significant difference between northern and southern cities. Fine particles were found to account for a large proportion of airborne particles, with the ratio of PM2.5 to PM10 ranging from 55% to 77%. The concentrations of PM2.5 (57.5 microg/m3) and PM10 (91.2 microg/m3) were much higher than the values (PM2.5: 11.2 microg/m3; PM10: 35.6 microg/m3) recommended by the World Health Organization. The attainment of the new urban air quality standard in the investigated cities is decreased by 20% in comparison with the older standard without considering O3, CO and PM2.5, suggesting a great challenge in urban air quality improvement, and more efforts will to be taken to control air pollution in China.
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Monóxido de Carbono/análise , Óxidos de Nitrogênio/análise , Ozônio/análise , Material Particulado/análise , Dióxido de Enxofre/análise , Monóxido de Carbono/normas , China , Cidades/estatística & dados numéricos , Gases/análise , Óxidos de Nitrogênio/normas , Ozônio/normas , Material Particulado/normas , Dióxido de Enxofre/normasRESUMO
Metal-organic frameworks (MOFs) have emerged as promising platforms for photocatalytic hydrogen evolution reaction (HER) due to their fascinating physiochemical properties. Rationally engineering the compositions and structures of MOFs can provide abundant opportunities for their optimization. In recent years, high-entropy materials (HEMs) have demonstrated great potential in the energy and environment fields. However, there is still no report on the development of high-entropy MOFs (HE-MOFs) for photocatalytic HER in aqueous solution. Herein, the authors report the synthesis of a novel p-type HE-MOFs single crystal (HE-MOF-SC) and the corresponding HE-MOFs nanosheets (HE-MOF-NS) capable of realizing visible-light-driven photocatalytic HER. Both HE-MOF-SC and HE-MOF-NS exhibit higher photocatalytic HER activity than all the single-metal MOFs, which are supposed to be ascribed to the interplay between the different metal nodes in the HE-MOFs that enables more efficient charge transfer. Moreover, impressively, the HE-MOF-NS demonstrates much higher photocatalytic activity than the HE-MOF-SC due to its thin thickness and enhanced surface area. At optimum conditions, the rate of H2 evolution on the HE-MOF-NS is ≈13.24 mmol h-1 g-1, which is among the highest values reported for water-stable MOF photocatalysts. This work highlights the importance of developing advanced high-entropy materials toward enhanced photocatalysis.
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The development of necroptosis inhibitors has emerged as a promising strategy to effectively mitigate necroptosis-related inflammatory diseases, neurodegenerative diseases, and cancers. In this paper, we reported a series of 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole derivatives as potent necroptosis inhibitors. The representative compound 26 displayed potent anti-necroptotic activity in both human and mouse cellular assays and exhibited potent inhibitory activity against receptor-interacting protein kinase 1 (RIPK1). In vivo pharmacokinetic studies were performed to determine the oral exposure of compound 26. Finally, molecular docking elucidated that compound 26 could effectively bind to the allosteric pocket of RIPK1 and serve as a type III inhibitor. Taken together, our findings highlighted that compound 26 represented a promising lead compound for future necroptosis inhibitor development.
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Hematopoietic progenitor kinase 1 (HPK1) is a key negative regulator of T-cell receptor (TCR) signaling and a promising target for cancer immunotherapy. The development of novel HPK1 inhibitors is challenging yet promising. In this study, we used a combination of machine learning (ML)-based virtual screening and free energy perturbation (FEP) calculations to identify novel HPK1 inhibitors. ML-based screening yielded 10 potent HPK1 inhibitors (IC50 < 1 µM). The FEP-guided modification of the in-house false-positive hit, DW21302, revealed that a single key atom change could trigger activity cliffs. The resulting DW21302-A was a potent HPK1 inhibitor (IC50 = 2.1 nM) and potently inhibited cellular HPK1 signaling and enhanced T-cell function. Molecular dynamics (MD) simulations and ADME predictions confirmed DW21302-A as candidate compound. This study provides new strategies and chemical scaffolds for HPK1 inhibitor development.Communicated by Ramaswamy H. Sarma.
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The receptor tyrosine kinase AXL has emerged as an attractive target in anticancer drug discovery. Herein, we described the discovery of a new series of 1,6-naphthyridin-4-one derivatives as potent AXL inhibitors. Starting from a low in vivo potency compound 9 which was previously reported by our group, we utilized structure-based drug design and scaffold hopping strategies to discover potent AXL inhibitors. The privileged compound 13c was a highly potent and orally bioavailable AXL inhibitor with an IC50 value of 3.2 ± 0.3 nM. Compound 13c exhibited significantly improved in vivo antitumor efficacy in AXL-driven tumor xenograft mice, causing tumor regression at well-tolerated dose, and demonstrated favorable pharmacokinetic properties (MRT = 16.5 h, AUC0-∞ = 59,815 ng h/mL) in Sprague-Dawley rats. These results suggest that 13c is a promising therapeutic candidate for AXL-targeting cancer treatment.
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Receptor Tirosina Quinase Axl , Neoplasias , Ratos , Humanos , Camundongos , Animais , Proteínas Proto-Oncogênicas , Ratos Sprague-Dawley , Receptores Proteína Tirosina Quinases , Inibidores de Proteínas Quinases/farmacocinética , Linhagem Celular Tumoral , Proliferação de CélulasRESUMO
To evaluate the measurement accuracy of horizontal and vertical remote emission sensing (RES) equipment, a real-world dynamic test was carried out in Chengdu by using electric vehicles equipped with various concentrations of standard gases. In addition, a new Image-based Spectral Processing Algorithm (ISPA) for vertical remote sensing spectral data was developed to improve the measurement capability. The results showed that the ISPA provided a greater percentage of valid data and lower relative errors; thus, our new algorithm could more effectively analyze the spectral data to measure vehicle emission levels. The percentages of valid horizontal and vertical RES data were 71% and 84%, respectively. The mean relative errors of CO2, CO, HC and NO measured by the vertical RES were about 5%, 20%, 20% and 40%, respectively, and those of CO2, CO and NO measured by the horizontal RES were 3%, 13% and 15%, respectively. For the common vehicle emission concentration, the percentage of valid data for the two RES types increased with increasing gas concentration. As the vehicle speed increased, the relative errors of the horizontal RES equipment showed an increasing trend for the same concentration of gas. Furthermore, for the same speed segment, the relative errors of the horizontal RES equipment increased as the simulated emission concentration decreased. The vertical RES equipment did not exhibit a consistent trend in terms of changes. This study provides a data quality reference for further RES applications.