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KRAS is the most frequently dysregulated oncogene with high prevalence in NSCLC, colorectal cancer, and pancreatic cancer. FDA-approved sotorasib and adagrasib provide breakthrough therapies for cancer patients with KRASG12C mutation. However, there is still high unmet medical need for new agents targeting broader KRAS-driven tumors. An emerging and promising opportunity is to develop a pan KRAS inhibitor by suppressing the upstream protein SOS1. SOS1 is a key activator of KRAS and facilitates the conversion of GDP-bound KRAS state to GTP-bound KRAS state. Binding to its catalytic domain, small molecule SOS1 inhibitor has demonstrated the ability to suppress KRAS activation and cancer cell proliferation. RGT-018, a potent and selective SOS1 inhibitor, was identified with optimal drug-like properties. In vitro, RGT-018 blocked the interaction of KRAS:SOS1 with single digit nM potency and is highly selective against SOS2. RGT-018 inhibited KRAS signaling and the proliferation of a broad spectrum of KRAS-driven cancer cells as a single agent in vitro. Further enhanced anti-proliferation activity was observed when RGT-018 was combined with MEK, KRASG12C, EGFR or CDK4/6 inhibitors. Oral administration of RGT-018 inhibited tumor growth and suppressed KRAS signaling in tumor xenografts in vivo. Combination with MEK or KRASG12C inhibitors led to significant tumor regression. Furthermore, RGT-018 overcame the resistance to the approved KRASG12C inhibitors caused by clinically acquired KRAS mutations either as a single agent or in combination. RGT-018 displayed promising pharmacological properties for combination with targeted agents to treat a broader KRAS-driven patient population.
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A solution-gate controlled thin-film transistor with SnO2 epitaxial thin films (SnO2-SGTFT) is successfully utilized for highly sensitive detection of nitrite. The SnO2 films are deposited as channel materials on a c-plane sapphire (c-Al2O3) substrate through pulsed laser deposition (PLD), with superior crystal quality and out-of-plane atomic ordering. PtAu NPs/rGO nanocomposites are electrodeposited on a gold electrode to function as a transistor gate to further enhance the nitrite catalytic performance of the device. The change in effective gate voltage due to the electrooxidation of nitrite on the gate electrode is the primary sensing mechanism of the device. Based on the inherent amplification effect of transistors, the superior electrical properties of SnO2, and the high electrocatalytic activity of PtAu NPs/rGO, the SnO2-SGTFT sensor has a low detection limit of 0.1 nM and a wide linear detection range of 0.1 nM ~ 50 mM at VGS = 1.0 V. Furthermore, the sensor has excellent characteristics such as rapid response time, selectivity, and stability. The practicability of the device has been confirmed by the quantitative detection of nitrite in natural lake water. SnO2 epitaxial films grown by PLD provide a simple and efficient way to fabricate nitrite SnO2-SGTFT sensors in environmental monitoring and food safety, among others. It also provides a reference for the construction of other high-performance thin-film transistor sensors.
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Correction for 'Single molecule magnet features in luminescent lanthanide coordination polymers with heptacoordinate Dy/Yb(III) ions as nodes' by Xiang-Tao Dong et al., Dalton Trans., 2023, 52, 12686-12694, https://doi.org/10.1039/D3DT02106H.
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PI3Kα is a lipid kinase that phosphorylates PIP2 and generates PIP3. The hyperactive PI3Kα mutation, H1047R, accounts for about 14% of breast cancer, making it a highly attractive target for drug discovery. Here, we report the cryo-EM structures of PI3KαH1047R bound to two different allosteric inhibitors QR-7909 and QR-8557 at a global resolution of 2.7 Å and 3.0 Å, respectively. The structures reveal two distinct binding pockets on the opposite sides of the activation loop. Structural and MD simulation analyses show that the allosteric binding of QR-7909 and QR-8557 inhibit PI3KαH1047R hyper-activity by reducing the fluctuation and mobility of the activation loop. Our work provides a strong rational basis for a further optimization and development of highly selective drug candidates to treat PI3KαH1047R-driven cancers.
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Microscopia Crioeletrônica , Simulação de Dinâmica Molecular , Humanos , Regulação Alostérica , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/química , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Ligação Proteica , Sítios de Ligação , Sítio Alostérico , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/químicaRESUMO
A Prussian blue analogue was synthesized using biomass leather waste as a precursor by doping with Co2+ ions. This material, demonstrates good performance in both the oxygen reduction reaction and oxygen evolution reaction, and exhibits excellent charge-discharge performance and stability in zinc-air batteries.
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In this study, two polymorphs of the [1,1'-dibutyl-4,4'-bipyridinium][Ni(mnt)2] salt (1) were synthesized. The dark-green polymorph (designated as 1-g) was prepared under ambient conditions by the rapid precipitation method in aqueous solutions. Subsequently, the red polymorph (labeled as 1-r) was obtained by subjecting 1-g to ultrasonication in MeOH at room temperature. Microanalysis, infrared spectroscopy, thermogravimetry (TG), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD) techniques were used to characterize the two polymorphs. Both 1-g and 1-r exhibit structural phase transitions: a reversible phase transition at â¼403 K (â¼268 K) upon heating and 384 K (â¼252 K) upon cooling for 1-g (1-r) within the temperature range below 473 K. Interestingly, on heating 1-r to 523 K, an irreversible phase transition occurred at about 494 K, resulting in the conversion of 1-r into 1-g. Relative to 1-r, 1-g represents a thermodynamically metastable phase wherein numerous high-energy conformations in butyl chains of cations are confined within the lattice owing to quick precipitation or rapid annealing from higher temperatures. Through variable-temperature single crystal and powder X-ray diffractions, UV-visible spectroscopy, dielectric spectroscopy, and DSC analyses, this study delves into the mechanism underlying phase transitions for each polymorph and the manual transformation between 1-g and 1-r as well.
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Metal-organic framework (MOF) membranes with rich functionality and tunable pore system are promising for precise molecular separation; however, it remains a challenge to develop defect-free high-connectivity MOF membrane with high water stability owing to uncontrollable nucleation and growth rate during fabrication process. Herein, we report on a confined-coordination induced intergrowth strategy to fabricate lattice-defect-free Zr-MOF membrane towards precise molecular separation. The confined-coordination space properties (size and shape) and environment (water or DMF) were regulated to slow down the coordination reaction rate via controlling the counter-diffusion of MOF precursors (metal cluster and ligand), thereby inter-growing MOF crystals into integrated membrane. The resulting Zr-MOF membrane with angstrom-sized lattice apertures exhibits excellent separation performance both for gas separation and water desalination process. It was achieved H2 permeance of ~1200 GPU and H2/CO2 selectivity of ~67; water permeance of ~8â L â m-2 â h-1 â bar-1 and MgCl2 rejection of ~95 %, which are one to two orders of magnitude higher than those of state-of-the-art membranes. The molecular transport mechanism related to size-sieving effect and transition energy barrier differential of molecules and ions was revealed by density functional theory calculations. Our work provides a facile approach and fundamental insights towards developing precise molecular sieving membranes.
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Heterostructure engineering and oxygen vacancy engineering are the most promising modification strategies to reinforce the Zn2+ ion storage of vanadium oxides. Herein, a rare mixed-dimensional material (VOx), composed of V2O5 (2D), V3O7 (3D), and V6O13 (3D) heterostructures, rich in oxygen vacancies, was synthesized via thermal decomposition of layered ammonium vanadate. The VOx cathode provides an exceptional discharge capacity (411 mA h g-1 at 0.1 A g-1) and superior cycling stability (the capacity retention remains close to 100% after 800 cycles at 2 A g-1) for aqueous zinc-ion batteries (AZIBs). Ex situ characterizations confirm that the byproduct Zn3V2O7(OH)2·nH2O is generated/decomposed during discharge/charge processes. Furthermore, VOx demonstrates reversible intercalation/deintercalation of H+/Zn2+ ions, enabling efficient energy storage. Remarkably, a reversible crystal-to-amorphous transformation in the V2O5 phase of VOx during charge-discharge was observed. This investigation reveals that mixed-dimensional heterostructured vanadium oxide, with abundant oxygen vacancies, serves as a highly promising electrode material for AZIBs, further advancing the comprehension of the storage mechanism within vanadium-based cathode materials.
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The supramolecular crystals, Mn(15-crown-5)(MnCl4)(DMF), (1; 15-crown-5 = 1,4,7,10,13-pentaoxacyclopentadecane), were synthesized via a self-assembly strategy under ambient conditions. Comprehensive characterization of the crystals involved microanalysis for C, H, and N elements, thermogravimetric (TG) analysis, differential scanning calorimetry (DSC) and single-crystal X-ray diffraction techniques. The results reveal that 1 undergoes a two-step thermotropic and isostructural phase transition at around 217 K and 351 K upon heating. All three phases belong to the same space group (P212121) with analogous cell parameters. These two phase transitions primarily involve the thermally activated ring rotational dynamics of the 15-crown-5 molecule, with only the transition at ca. 351 K being associated with a dielectric anomaly. 1 exhibits intense luminescence with a peak at â¼600 nm and a high quantum yield of 68%. The mechanisms underlying this intense luminescence are likely linked to low-symmetry ligand fields. Additionally, 1 displays phase transition-induced luminescence enhancement behavior, and the possible mechanism is further discussed.
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Solid proton electrolytes play a crucial role in various electrochemical energy storage and conversion devices. However, the development of fast proton conducting solid proton electrolytes at ambient conditions remains a significant challenge. In this study, a novel acidified nitrogen self-doped porous carbon material is presented that demonstrates exceptional superprotonic conduction for applications in solid-state proton battery. The material, designated as MSA@ZIF-8-C, is synthesized through the acidification of nitrogen-doped porous carbon, specifically by integrating methanesulfonic acid (MSA) into zeolitic imidazolate framework-derived nitrogen self-doped porous carbons (ZIF-8-C). This study reveals that MSA@ZIF-8-C achieves a record-high proton conductivity beyond 10-2 S cm-1 at ambient condition, along with good long-term stability, positioning it as a cutting-edge alternative solid proton electrolyte to the default aqueous H2 SO4 electrolyte in proton batteries.
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Two sets of 1D/2D lanthanide coordination polymers with formulas of Ln(oqa)3·2H2O [Hoqa = 2-(4-oxoquinolin-1(4H)-yl) acetic acid, Ln = Dy (1), Yb (2)] and Ln(oaa)2(HCOO)(H2O) [Hoaa = 2-(9-oxoacridin-10(9H)-yl) acetic acid, Ln = Dy (3), Yb (4)] have been synthesized and their physical properties were investigated. All four complexes are constructed from seven-coordinate lanthanide ions and corresponding organic linkers. The lanthanide ions in 1 and 2 adopt a pentagonal bipyramid coordination geometry, whereas the coordination geometry of lanthanide ions in 3 and 4 can be described as a capped octahedron. Slow magnetic relaxation behaviors were observed in these four products at a zero/non-zero static magnetic field. Complexes 1, 2 and 4 exhibit the characteristic emission of Ln(III) ions, whereas complex 3 shows ligand-based emission. Bright yellow light emission was also observed when a voltage was applied, demonstrating the potential of 1 for application in light-emitting diodes (LEDs). Compounds 3 and 4 are the first examples of lanthanide complexes based on Hoaa ligands.
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Here, spinodal decomposition is used as a strategy to enhance the mechanical properties of the 30Al2O3·70SiO2 glass. The melt-quenched 30Al2O3·70SiO2 glass exhibited a liquid-liquid phase separation with an interconnected snake-like nano-structure. Through further heat treatment at 850 °C for different durations of up to 40 hours, we observed a continuous increase of up to about 0.90 GPa in hardness (Hv) together with a drop in the slope for Hv rise at 4 hours. However, the crack resistance (CR) achieved a maximum value of 13.6 N when the heat treatment time was 2 hours. Detailed calorimetric, morphological and compositional analyses were conducted to elucidate the effect of tuning the thermal treatment time on hardness and crack resistance. These findings pave the way to utilize the spinodal phase-separated phenomena to enhance the mechanical properties of glasses.
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Two haloargentate hybrids, [Me-dabco]Ag2X3 (Me-dabco = 1-methyl-1,4-diazabicyclo-[2.2.2]octan-1-ium, X = I (1) or Br (2)), with the same formula but different structures have been synthesized by a slow evaporation method and characterized by microanalysis, infrared spectroscopy, thermogravimetric, and powder X-ray diffraction techniques. Hybrid 1 consists of completely isolated [Ag4I6]2- clusters, while hybrid 2 exhibits a complicated one-dimensional (1D) chain structure formed by four different configurations of neutral chains and two dissimilar configurations of anionic chains. Hybrid 2 undergoes two reversible order-disorder phase transitions, while hybrid 1 displays one reversible and one irreversible structural phase transition. Both 1 and 2 displayed step-like dielectric anomalies in the vicinity of the phase transition temperature. The corresponding dielectric constants in the high dielectric states are approximately 13 and 6 times higher than those in the low dielectric states for 1 and 2, respectively. Interestingly, the subtle change of halides from I- to Br- significantly affects the aggregated structure of haloargentate, the phase transition, and dielectric behaviors, revealing the typical 'butterfly effect' with the ion radii of halides in these two haloargentate hybrids.
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A thermochromic or mechanochromic material can switch between at least two stable states in response to changes in temperature or static pressure/strain. In this study, we investigated a Ni-dithiolene dianion salt, 1,1'-diheptyl-4,4'-bipyridinium bis(maleonitriledithiolato)nickelate (1), and found that its cations and anions stack alternately to form a uniform mixed stack. These mixed stacks then combine to form a molecular solid through Coulomb and van der Waals interactions. Upon heating, 1 undergoes a reversible phase transition at around 340/320 K during the first heating/cooling cycle, resulting in rapid thermochromism with a color change from green (stable state) to red (metastable state) within a few seconds. This is the first report of a crystal of bis(maleonitriledithiolato)nickelate(II) salt with green color. Additionally, 1 exhibits irreversible mechanochromism, intense near-IR absorbance, and a dielectric anomaly. The structural phase transition is responsible for these properties, as it induces alterations in the π-orbital overlap between the anion and cation within a mixed stack. The intense near-IR absorbance arises from the ion-pair charge transfer transition from [Ni(mnt)2]2- to 4,4'-bipyridinium.
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Herein, we demonstrated the unique advantage of a mechanochemical reaction to prepare a salt with hard and soft acid and base ions concurrently by solution synthesis owing to the soft acid preferring to combine with the soft base and vice versa. We prepared Bu4N1-xLixMnxPb1-xI3 (x = 0.011-0.14) by mechanochemical synthesis. The doping induced a structural phase transition at â¼342 K and much enhancement of ionic conduction above 342 K for all co-doped hybrids regarding Bu4NPbI3 because of the voids around the Mn2+/Li+ ions by doping.
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In order to get stable co-continuous morphology in immiscible polymer blends, besides reducing the interfacial tension, the compatibilizer should not only promote the formation of flat interface between different phases, but also not hinder the coalescence of the dispersed phase. Herein, the relationship between the morphology of the compatibilized polystyrene/nylon 6/styrene-maleic anhydride (PS/PA6/SMA) immiscible polymer blends and the structures of the in-situ formed SMA-g-PA6 graft copolymers as well as the processing conditions are studied. Two kinds of SMA are used: SMA28 (28 wt.% MAH) and SMA11 (11 wt.% MAH). After melt blending with PA6, the in-situ formed copolymer SMA28-g-PA6 has on average of four PA6 side chains, while that of SMA11-g-PA6 has only one. Dissipative particle dynamics simulation results indicate that both SMA28-g-PA6 copolymer and PS/PA6/SMA28 blends tend to form co-continuous structure, while those related to SMA11 intend to form sea-island morphologies. These results are correct only at relatively low rotor speed (60 rpm). When the rotor speed is higher (105 rpm), sea-island morphologies are obtained in SMA28 systems, while that for SMA11 ones are co-continuous. This indicates that higher shear stress can elongate the minor phase domains to form flat interfaces, while the SMA28-g-PA6 copolymers can be pulled out from the interface.
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Polímeros , Poliestirenos , Polímeros/química , Poliestirenos/químicaRESUMO
Selective CDK2 inhibitors have the potential to provide effective therapeutics for CDK2-dependent cancers and for combating drug resistance due to high cyclin E1 (CCNE1) expression intrinsically or CCNE1 amplification induced by treatment of CDK4/6 inhibitors. Generative models that take advantage of deep learning are being increasingly integrated into early drug discovery for hit identification and lead optimization. Here we report the discovery of a highly potent and selective macrocyclic CDK2 inhibitor QR-6401 (23) accelerated by the application of generative models and structure-based drug design (SBDD). QR-6401 (23) demonstrated robust antitumor efficacy in an OVCAR3 ovarian cancer xenograft model via oral administration.
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Initiating explosive (IE) devices are widely used in the aerospace, resource mining, and basic industries and other fields. With the improvement in processing technology, IE devices are developing towards miniaturization and intelligence. As an important component of the energy conversion of IE devices, the output characteristics of micro energy conversion (EC) elements directly affect the ignition performance of IE devices. Hence, this paper researches the output characteristics of EC elements under external excitation. Firstly, the fabrication process of the EC element is introduced, and the finite element analysis model of the temperature field is deduced. Secondly, the simulation model of the output characteristics of the EC element is constructed, the validity of the model is verified through experiments, and the basic characteristic parameters of the EC element are determined. Finally, four shapes of EC element structures are designed, the corresponding output characteristics under constant current excitation are analyzed, and the temperature and current field distributions of the EC elements with different shapes are given. The experimental and simulation results show the effectiveness of the analysis results in this paper, and the influence of different shapes on the insensitivity of EC elements is given through comparative analysis, which provides support for the design of micro structure EC elements.
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Stimuli-responsive smart materials have applications in a range of technologies. Herein, we present a hybrid (1), built from Me3EtN+ organic cations and {Cu2I3-}∞ inorganic chains with Cuâ¯Cu metalâ¯metal interactions. The two-step phase transition undergone in 1 on the first heating and the phase transition at a lower temperature show symmetry-broken features, leading to switchable dielectrics; the one at a higher temperature displays isomorphic characteristics. Besides the switchable dielectrics, 1 exhibited other multi-stimuli-responsive functionalities, including thermochromism and piezochromism. Combining temperature-dependent powder and single crystal X-ray diffraction, as well as variable-temperature UV-visible absorption spectrum and EPR spectrum analyses, it is demonstrated that the thermochromism is due to the synergy of anharmonic fluctuations with electron-phonon couplings, and the piezochromism arises from compression inducing a lattice distortion in 1. Our study provides insight into understanding the thermochromic and piezochromic mechanisms of cuprous halide-based hybrids, and paves a pathway for designing new multi-stimuli-responsive hybrid materials.
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Two organic-inorganic manganese(II) halide hybrids (OIMHs) with formulas of [(TEA)(TMA)]MnCl4 (1) and [(TPA)(TMA)3](MnCl4)2 (2) (TEA = tetraethylammonium, TMA = tetramethylammonium, and TPA = tetrapropylammonium) were synthesized by a mixed-ligand strategy. Both compounds crystallize in the acentric space group and are composed of isolated [MnCl4]2- tetrahedral units separated by two types of organic cations. They show high thermal stability and emit strong green light with different emission bandwidths, quantum yields, and high-temperature photostability. Remarkably, the quantum yield of 1 can reach up to 99%. Due to the high thermal stability and quantum yield of 1 and 2, green light-emitting diodes (LEDs) were fabricated. Furthermore, mechanoluminescence (ML) was observed in 1 and 2 when stress was applied. The ML spectrum of 1 is similar to the photoluminescence (PL) spectrum, suggesting ML and PL emissions come from the same transition of Mn(II) ions. Finally, rewritable anticounterfeiting printing and information storage were achieved by utilizing the outstanding photophysical properties and ionic features of the products. The printed images still remain clear after several cycles, and the information stored on the paper can be read out by a UV lamp and commercial mobile phones.