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GH738 superalloy offers exceptional material properties at elevated temperature and is widely applied to the critical components of aero-engines and gas turbine. However, high strength and poor thermal conductivity bring significant challenges for the machining and surface qualities of GH738 superalloy. In this work, the creep feed grinding performance of GH738 was investigated. The variation laws and formation mechanism of surface integrity were explored with three common types of alumina grinding wheels under various grinding parameters. The experimental results showed that there is considerable impact of grinding parameters on the grinding force and grinding temperature. The stronger coupling of thermal and mechanical aggravates worse surface integrity. The propensity of grinding burn could be more sensitive when the maximum undeformed chip thickness is greater than 0.45–0.5 μm. With the material removal rate in the range of 0.83–1.67 mm3/mm·s, surface defects are visible, and the thickness of plastic deformation layer is about 4–6 μm. In addition, the surface quality ground by the white and pink fused alumina mixed abrasive grinding wheel (WA-PA) is slightly superior to that of the WA and BA grinding wheels. Finally, the grinding parameters for creep feed grinding GH738 are recommended as vw ∈ [50, 150] mm/min, vs ∈ [25, 35] m/s, and ap ∈ [0.2, 0.6] mm. [ABSTRACT FROM AUTHOR]

In the heterogeneous catalysis, adsorption and desorption behaviors of reactants and products on the surface of catalysts can remarkably impact their catalytic activities and product selectivities. Here, series of Ru‐based catalysts supported on Zn‐incorporated Li−Al layered double hydroxides (Ru/LDH) were developed and employed in the selective benzene hydrogenation to produce cyclohexene without the use of any additional zinc salt additives. It was demonstrated that as‐constructed supported Ru catalyst bearing a Zn/(Li+Zn) molar ratio of 0.075 in the LDH support gave a higher cyclohexene yield of 43.2 % than those over other Ru‐based ones. Combining structural characterizations and catalytic hydrogenation reactions with temperature‐programmed desorption and in situ Fourier transform infrared spectroscopy of benzene and cyclohexene, it was revealed that the generation of appropriate surficial/interfacial Ru0/Ruδ+−O−Zn structures, as well as the existence of abundant hydroxyl groups on LDH supports, could facilitate the benzene adsorption and the cyclohexene desorption, thereby remarkably promoting the formation of cyclohexene. The present findings not only give a profound insight into the roles of surface‐interface structures of supported Ru catalysts for efficient benzene hydrogenation to produce cyclohexene but also simultaneously provide a promising guide to design high‐performance Ru‐based catalysts. [ABSTRACT FROM AUTHOR]

• Antidepressants can be potentially repurposed for anticancer drug discovery. • Antidepressants exhibit the antitumor activity with different mechanisms. • Repurposing tranylcypromine has led to the discovery of LSD1 inhibitors for cancer therapy. • Repurposing antidepressants may provide hopes for patients suffering from depression and cancers simultaneously. Drug repurposing is an attractive strategy for identifying new indications for existing drugs. Three approved antidepressants have advanced into clinical trials for cancer therapy. In particular, further medicinal chemistry efforts with tranylcypromine (TCP) have led to the discovery of several TCP-based histone lysine specific demethylase 1 (LSD1) inhibitors that display therapeutic promise for treating cancer in the clinic. Thus repurposing antidepressants could be a promising strategy for cancer treatment. In this review, we illustrate the anticancer mechanisms of action of antidepressants and also discuss the challenges and future directions of repurposing antidepressants for anticancer drug discovery, to provide an overview of approved antidepressant cancer therapies. [ABSTRACT FROM AUTHOR]

Cu/ZnO/Al 2 O 3 catalysts have been widely applied as industrial catalysts for methanol synthesis from syngas, but suffers low activity for CO 2 hydrogenation to methanol. This study establishes highly active Cu catalysts through modulation of the composite of Al 2 O 3 and ZrO 2 in Cu/ZnO-based catalysts. The composition of Al 2 O 3 and ZrO 2 impacts the Cu dispersion, exposed surface area of Cu, the Cu0/(Cu0+Cu+) ratio and surface basicity. An appropriate content of Al 2 O 3 and ZrO 2 presents the higher Cu surface area, desirable ratio of Cu0/(Cu0+Cu+) and moderate-strong basic sites for effective CO 2 adsorption/activation, giving rise to higher space-time yield of methanol (up to 648 g CH3OH ·kg cat −1·h−1) than the commercial Cu catalyst. STY of methanol can be correlated with Cu surface area and Cu0/(Cu0+Cu+) ratio under the investigated conditions. The mechanistic analysis demonstrates that surface formate and methoxy species are the major intermediates. The methanol formation principally follows the formate-methoxy intermediate pathway. [Display omitted] • An appropriate amount of Al 2 O 3 and ZrO 2 favors the production of methanol. • The conversion rate of CO 2 is positively correlated with S Cu. • The relatively high content of Cu0 showed higher activity. • The increase of the number of moderate basic sites contributes to the improvement of CO 2 conversion rate. • The CO 2 hydrogenation to methanol followed the formate intermediate pathway. [ABSTRACT FROM AUTHOR]

The function of signal regulatory protein alpha (SIRPA) has been well studied in macrophages and dendritic cells, but relatively less in tumors. Notably, SIRPA is upregulated in osteosarcoma tissues, particularly in metastatic tissues, and is associated with unfavorable clinical outcomes. Knockdown of SIRPA impaired OS cell migration by decreasing specificity protein 1 (SP1) stability and arginine uptake. Importantly, SIRPA phosphorylated SP1 at threonine 278 (Thr278) through extracellular signal-regulated kinase (ERK) activation to protect SP1 from proteasomal degradation. In addition, SP1 increased solute carrier family 7 member 3 (SLC7A3) expression by binding to the SLC7A3 promoter and increased the capability of arginine uptake, thereby facilitating OS cell migration. More interestingly, arginine promoted the stability of SP1 in an ERK-independent manner and thus formed the "SP1 stabilization circle". Combined treatment with the anti-SIRPA antibody and arginase, which blocked the circle, impaired tumor metastasis in mice bearing xenografts formed from SIRPA-overexpressing cells. In summary, our study demonstrates that the upregulation of SIRPA promotes OS metastasis via the "SP1 stabilization circle" and SLC7A3-mediated arginine uptake, which might serve as a target for OS treatment. • SIRPA is overexpressed in high active osteosarcoma and promotes metastasis. • SIRPA enhances the expression of SLC7A3 and facilitate arginine utilization. • SIRPA increases SP1 stability via phosphorylation of SP1 at Thr273. • SP1 stabilization cycle plays a key role in the metastasis in OS. • Combination therapy targeting both SIRPA and arginine inhibits tumor metastasis. [ABSTRACT FROM AUTHOR]

The cAMP response element (CRE) binding protein (CREB) is central in the transcription regulation by cAMP, and the CREB-regulated transcriptional coactivators (CRTCs) play critical roles in CREB-mediated transcription activation. Upon stimulation, CRTCs translocate into the nucleus and complex with CREB on CRE promoters to activate target gene transcription. Their physiological importance is underscored by their function in energy balance, long-term memory, longevity and other processes. The CREB binding domain on CRTCs has been mapped, which interacts with the CREB basic leucine zipper domain that also mediates interaction with CRE-containing DNA. We report here crystal structures of a complex containing the CRTC2 CREB binding domain, the CREB basic leucine zipper domain and a CRE-containing DNA. The structures revealed that CRTC and CREB form a 2:2 complex on CRE-containing DNA, and CRTC interacts with both CREB and DNA through highly conserved residues. Structure-guided functional studies revealed that both interactions are crucial for the complex assembly and CREB stabilization on DNA. Interestingly, we found that the CRTC–DNA interaction confers selectivity toward the intrinsic DNA shape, which may play a role in selective transcription activation of the CRE genes. [ABSTRACT FROM AUTHOR]

Deubiquitinating enzyme ubiquitin-specific protease 7 (USP7) is a promising therapeutic target. Several USP7 inhibitors accommodated in the catalytic triad of USP7 have been reported with the aid of high-throughput screening (HTS) methods using USP7 catalytic domain truncation. However, the drawbacks of previously reported biochemical cleavage assays, including poor stability, fluorescence interference, time-consuming, expensive, more importantly the selectivity issue, have challenged the USP7-targeted drug discovery. In this work, we demonstrated the functional heterogeneity and essential role of different structural elements in the USP7 full activation, highlighting the necessity of USP7 full length in drug discovery. Apart from reported two pockets in the catalytic triad, five additional ligandable pockets were predicted based on the proposed USP7 full length models by AlphaFold and homology modelling. A reliable homogeneous time-resolved fluorescence (HTRF) HTS method was established based on the cleavage mechanism of USP7 towards the ubiquitin precursor UBA10. The USP7 full length protein was successfully expressed in the relatively cost-effective E. coli prokaryotic system and used to simulate the auto-activated USP7 in nature. Via screening our in-house library (∼ 1500 compounds), 19 hit compounds with >20% of inhibition rate were identified for further optimization. This assay will enrich the toolbox for the identification of highly potent and selective USP7 inhibitors for clinical use. [Display omitted] • Five additional ligandable pockets were predicted based on the proposed USP7 full length models. • The functional heterogeneity of different structural elements in the full activation of USP7 is highlighted. • The catalytic activity of recombinant USP7 full length protein expressed in E. coli prokaryotic system is characterized. • A reliable and cost-effective HTRF HTS method was established using the E. coli expressed USP7 full length protein. • 19 Hit compounds were identified from our in-house library for further optimization. [ABSTRACT FROM AUTHOR]

Phosphorylation is a reversible post-translational modification regulated by phosphorylase and dephosphorylase to mediate important cellular events. Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) encoded by PTPN11 is the first identified oncogenic protein in protein tyrosine phosphatases family. Serving as a convergent node, SHP2 is involved in multiple cascade signaling pathways including Ras-Raf-MEK-ERK, PI3K-AKT, JAK-STAT and PD-1/PD-L1 pathways. Especially, the double-edged roles of SHP2 based on the substrate specificity in various biological contexts dramatically increase the effect complexity in different SHP2-associated diseases. Evidences suggest that by collaborating with other mutations in associated pathways, dysregulation of SHP2 contributes to the pathogenesis of different cancers, making SHP2 a promising therapeutic target for cancer treatment. SHP2 can either act as oncogenic factor or tumor suppressor in different diseases, and both the conserved catalytic dephosphorylation mechanism and the unique allosteric regulation mechanism of SHP2 provide opportunities for the development of SHP2 inhibitors and activators. To date, several small-molecule SHP2 inhibitors have advanced into clinical trials for mono- or combined therapy of cancers. Moreover, SHP2 activators and proteolysis-targeting chimera (PROTAC)-based degraders also display therapeutic promise. In this review, we comprehensively summarize the overall structures, regulation mechanisms, double-edged roles of SHP2 in both physiological and carcinogenic pathways, and SHP2 inhibitors in clinical trials. SHP2 activators and degraders are also briefly discussed. This review aims to provide in-depth understanding of the biological roles of SHP2 and highlight therapeutic potential of targeting SHP2. [ABSTRACT FROM AUTHOR]

Lysine-specific demethylase 1 (LSD1/KDM1A) has emerged as a promising epigenetic target for disease treatment. Several LSD1 inhibitors have advanced into clinical trials. Following our last annual review on LSD1 inhibitors in 2020 (Eur. J. Med. Chem. 2021, 214, 113254), in this review we aim to update LSD1 inhibitors including natural products, synthetic compounds and cyclic peptides reported during 2021. Design strategies, structure-activity relationships, binding model analysis and modes of action are highlighted. In particular, two FDA-approved antihypertensive drugs raloxifene and fenoldopam were repurposed as reversible LSD1 inhibitors. The clinical candidate TAK-418 for treating neurodevelopmental disorders and PET imaging agent [18F] 30 for LSD1 were identified. Moreover, dual inhibitors targeting both LSD1 and HDAC6 or tubulin displayed enhanced anti-cancer effects than single agents. These compounds further enrich the structural types of LSD1 inhibitors. [Display omitted] • LSD1 is a promising epigenetic target for disease treatment. • Compounds with novel scaffolds enrich the structural diversity of LSD1 inhibitors. • Clinical candidate TAK-418 shows therapeutic potential for neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]

As the interplanetary magnetic field (IMF) carried by the solar wind encounters the martian atmosphere, it tends to pile up and drape around the planet, forming looping magnetic fields and inducing marsward ion flows on the nightside. Previous statistical observations revealed asymmetrical distribution features within this morphology; however, the underlying physical mechanism remains unclear. In this study, utilizing a three‐dimensional multi‐fluid magnetohydrodynamic simulation model, we successfully reproduce the asymmetrical distributions of the looping magnetic fields and corresponding marsward flows on the martian nightside. Analyzing the magnetic forces resulting from the bending of the IMF over the polar area, we find that the asymmetry is guided by the orientation of the solar wind motional electric field (ESW). A higher solar wind velocity leads to enhanced magnetic forces, resulting in more tightly wrapped magnetic fields with an increased efficiency in accelerating flows as they approach closer to Mars. Plain Language Summary: As incident solar wind interacts with Mars, the entrained interplanetary magnetic field drapes and stretches around the planet. The draped fields are orientated in opposite directions on the east and west sides of Mars, resulting in magnetic reconnection, the formation of looping magnetic fields and induced marsward plasma flows on the nightside. Statistical observations suggest an asymmetric distribution of these structures, however, the underlying physical mechanisms for this asymmetry have not been determined due to limited spatial coverage offered by the single spacecraft investigations. In this study, by taking advantage of a Hall‐MHD model, we have successfully reproduced the asymmetrical distributions and elucidated the underlying mechanisms governing these morphologies. Simulation results demonstrate that magnetic forces tend to emerge around the polar region, which are determined by the orientation of the ESW, shifting the plasma flows and magnetic fields in the direction opposite to the motional electric field. A higher solar wind velocity condition will induce amplified magnetic forces, resulting in more tightly wrapped magnetic fields and an increase in the velocity of marsward flows closer to the martian nightside. These findings provide valuable insights into the influence of the ESW and solar wind velocity on the martian induced magnetosphere. Key Points: The asymmetrical distributions of looping magnetic fields and associated marsward flows can be well reproduced by a multi‐fluid magnetohydrodynamic (MHD) modelThe impacts of the motional electric field direction and the solar wind velocity on the asymmetries are investigated, respectivelyMagnetic forces shift the magnetic fields and marsward flows toward the direction opposite to the motional electric field [ABSTRACT FROM AUTHOR]

Chemoresistance is the main obstacle in the clinical treatment of osteosarcoma (OS). In this study, we investigated the role of EF-hand domain-containing protein 1 (EFHD1) in OS chemotherapy resistance. We found that the expression of EFHD1 was highly correlated with the clinical outcome after chemotherapy. We overexpressed EFHD1 in 143B cells and found that it increased their resistance to cell death after drug treatment. Conversely, knockdown of EFHD1 in 143BR cells (a cisplatin-less-sensitive OS cell line derived from 143B cells) increased their sensitivity to treatment. Mechanistically, EFHD1 bound to adenine nucleotide translocase-3 (ANT3) and inhibited its conformational change, thereby inhibiting the opening of the mitochondrial membrane permeability transition pore (mPTP). This effect could maintain mitochondrial function, thereby favoring OS cell survival. The ANT3 conformational inhibitor carboxyatractyloside (CATR), which can promote mPTP opening, enhanced the chemosensitivity of EFHD1-overexpressing cells when combined with cisplatin. The ANT3 conformational inhibitor bongkrekic acid (BKA), which can inhibit mPTP opening, restored the resistance of EFHD1 knockdown cells. In conclusion, our results suggest that EFHD1-ANT3-mPTP might be a promising target for OS therapy in the future. [ABSTRACT FROM AUTHOR]

The integral blisk has been widely used in aerospace, and its structural performance is inextricably linked to the blade surface quality. To improve the surface integrity of polished surface, ultrasonic vibration assisted belt flapwheel flexible polishing (UBFP) is proposed. In this study, the polishing principle of UBFP and the effects of vibration on surface generation are investigated, and kinematic analyses and trajectory simulations are performed. Furthermore, the influences of the main processing parameters on the polishing force and surface roughness in UBFP are explored experimentally, and the sensitivity of the main parameters is distinguished by multi-parameter relative sensitivity analysis based on Monte Carlo simulation. The results show that the ultrasonic vibration contributes to the polishing process primarily through kinematic state changing and trajectories interlacing of abrasives. Compared with conventional belt flapwheel flexible polishing, the polishing force decreases by 15.72% and the surface roughness decreases by 17.39%. The compression depth is the most sensitive parameter in the process of UBFP. This study demonstrates the feasibility of UBFP and provides a theoretical and experimental reference for improving the polishing surface quality of the blisk blade. [ABSTRACT FROM AUTHOR]

δ-MnO 2 was proposed as a promising cathode material for aqueous Zn-ion batteries. Nonetheless, its potential application has been impeded by its unstable crystal structure and sluggish reaction kinetics with Zn ions. Herein, we utilized Cr to modify δ-MnO 2 by a simple hydrothermal method to develop cathode materials for aqueous Zn-ion batteries with better stability and electron transport properties. The introduction of Cr enhanced the specific capacity and cycling stability of δ-MnO 2 , in particular, the 3% Cr doped δ-MnO 2 electrode exhibited a large specific capacity of 229.2 mAh·g−1 at 0.1 A·g−1 and an excellent capacitance retention of 86.0% after performing 300 cycles. The density functional theory (DFT) calculations indicate that the introduction of Cr decreases the band gap of MnO 2 and enhances electron migration in the electrode material. Meanwhile, the introduction of Cr substantially improved the Zn ion adsorption and enhanced the binding energy of δ-MnO 2 , indicating that the addition of Cr promoted the interaction between the Cr doping δ-MnO 2 (Cr-MnO 2) electrode materials with Zn ions, while making the structure of the electrode materials more stable. As a result, this suppresses the Jahn-Teller distortion and reduces the solvation and phase transition of Mn. [Display omitted] • A facile Cr doped strategy for δ-MnO 2 was used for aqueous Zn-ion battery. • Cr doped δ-MnO 2 electrode exhibited specific capacity of 229.3 mAh•g-1 at 0.1 A•g-1 and 86.0% retention after 300 cycles. • The doping of Cr ions reventing the lattice distortion and suppressing the Jahn-Teller distortion of Mn in δ-MnO 2. • The density functional theory calculations confirm a reduced bandgap and increased binding energy in Cr-MnO 2. [ABSTRACT FROM AUTHOR]

Longitudinal torsional ultrasonic-assisted grinding (LTUG) is one of the main methods to achieve high-quality and high-efficiency machining of high-performance ceramic materials. However, it isn't easy to accurately characterize the three-dimensional (3-D) surface topography due to multiple random factors during LTUG. Aiming at the complex surface features caused by multiple random factors in the LTUG of Si3N4 ceramics, a probabilistic algorithm for the height of residual material on the surface (HRMS) in LTUG of Si3N4 ceramic was proposed, and the prediction model for the 3-D surface topography and 3-D surface roughness parameters of Si3N4 ceramics in LTUG was established by using this algorithm. Simulation and experimental results show that the prediction model of 3-D surface topography and 3-D surface roughness established by the HRMS algorithm can more realistically predict the general characteristics of 3-D surface topography in LTUG under different process parameters, and the error range of the 3-D surface roughness parameter is 0–14.07%, which realizes the high-precision and high-reliability prediction of the 3-D surface topography and 3-D surface roughness parameters of the Si3N4 ceramic under LTUG. [ABSTRACT FROM AUTHOR]

SnO2‐x nanocrystals were prepared using a simple hydrothermal method by controlling the proportions of Sn4+/Sn2+ precursors. Due to the doping of Sn2+, the oxygen vacancies could be introduced into SnO2 nanocrystals, and their concentration can be controlled by the amount of doping Sn2+. The structural characteristics of SnO2‐x nanocrystals was investigated by X‐ray diffraction, Fourier transform infrared spectra, Raman spectra, UV‐vis diffuse reflectance, photoluminescence spectra and X‐ray photoelectron spectroscopy. The results reveal that the bridging O‐vacancies are dominant in the pure SnO2 while the in‐plane O‐vacancies play a key role in the SnO2‐x. Meanwhile, the higher Sn2+ concentration, the more structural disorder was produced. According to XPS analysis, the presence of oxygen defects will change the electronic structure of SnO2‐x nanocrystals, which will lead to the valence band moving up and the smaller band gap. The rich oxygen vacancies, the structural disorder and the narrow band gap should greatly improve the visible light harvesting, and result in the excellent photocatalytic activity. [ABSTRACT FROM AUTHOR]

Background: The zinc transporters Zrt- and Irt-related protein (ZIP/SLC39) are overexpressed in human tumors and correlate with poor prognosis; however, their contributions to carcinogenesis and chemoresistance in osteosarcoma (OS) remain unclear. Methods: We collected 64 OS patient tissues with (n = 12) or without (n = 52) chemotherapy. The expression levels of ZIP10 were measured by immunohistochemistry and applied to prognostic analysis. ZIP10 was knocked down or overexpressed in OS cell lines to explore its effect on proliferation and chemoresistance. RNA sequencing, quantitative real-time PCR, and western blotting analysis were performed to explore ZIP10-regulated downstream target genes. A xenograft mouse model was established to evaluate the mechanisms by which ZIP10 modulates chemoresistance in OS cells. Results: The expression of ZIP10 was significantly induced by chemotherapy and highly associated with the clinical outcomes of OS. Knockdown of ZIP10 suppressed OS cell proliferation and chemoresistance. In addition, ZIP10 promoted Zn content-induced cAMP-response element binding protein (CREB) phosphorylation and activation, which are required for integrin α10 (ITGA10) transcription and ITGA10-mediated PI3K/AKT pathway activation. Importantly, ITGA10 stimulated PI3K/AKT signaling but not the classical FAK or SRC pathway. Moreover, overexpression of ZIP10 promoted ITGA10 expression and conferred chemoresistance. Treatment with the CREB inhibitor 666–15 or the PI3K/AKT inhibitor GSK690693 impaired tumor chemoresistance in ZIP10-overexpressing cells. Finally, a xenograft mouse model established by subcutaneous injection of 143B cells confirmed that ZIP10 mediates chemotherapy resistance in OS cells via the ZIP10-ITGA10-PI3K/AKT axis. Conclusions: We demonstrate that ZIP10 drives OS proliferation and chemoresistance through ITGA10-mediated activation of the PI3K/AKT pathway, which might serve as a target for OS treatment. [ABSTRACT FROM AUTHOR]

[Display omitted] • High-surface-area and porous Ca-doped ZnAl2O4 supported Pt catalysts were fabricated. • As-fabricated Pt-based catalysts was highly active for base-free glycerol oxidation. • Glycerol was efficiently converted to glyceric acid with a high selectivity. • Synergy between electron-rich Pt species and basic sites contributed to its high efficiency. In the work, highly dispersed platinum nanocatalysts supported over undoped and Ca-doped zinc aluminate spinels were developed and applied for aqueous-phase selective oxidation of glycerol to produce glyceric acid under base-free conditions. As-fabricated Pt-based catalyst with the incorporation of an appropriate Ca/(Ca + Zn) molar ratio of 0.1 into the spinel exhibited a higher catalytic activity, along with a selectivity to glyceric acid (>81%) and a high turnover frequency of 1160 h−1, compared with other supported Pt-based ones over zinc aluminates, as well as most of supported Pt catalysts previously reported. The structural characterizations and catalytic experiments showed that surface synergy between highly dispersed metallic Pt0 species and medium-strength basic sites mainly contributed to its enhanced catalytic efficiency for base-free glycerol oxidation. Moreover, the present Pt catalyst also presented high structural stability and good reusability. The work opens an alternative approach for constructing highly efficient and stable metal-base bifunctional catalysts for a wide range of heterogeneous oxidation processes without the addition of liquid alkalis. [ABSTRACT FROM AUTHOR]

[Display omitted] • Compounds with new scaffolds further enrich the chemo-type diversity of LSD1 inhibitors. • The unique multiple-copies binding mode of quinazoline derivatives paves new way for the development of reversible LSD1 inhibitors by blocking the substrate entrance. • The structure–activity relationships of clinical candidate TAK-418 analogs may favor the design of novel irreversible LSD1 inhibitors with low hematological side effects. • The influence of compound stereochemistry on the potency against LSD1 and its homolog LSD2 provide direction for selective LSD1 inhibitors. Lysine-specific demethylase 1 (LSD1/KDM1A) dysregulation is closely associated with the pathological processes of various diseases, especially hematologic malignancies. Significant progresses have been made in the field of LSD1-targeted drug discovery. Nine LSD1 inhibitors including tranylcypromine, ORY-1001, ORY-2001, GSK-2879552, IMG-7289, INCB059872, TAK-418, CC-90011 and SP-2577 have entered clinical stage for disease treatment as either mono- or combinational therapy. This review updates LSD1 inhibitors reported during 2022. Design strategies, structure–activity relationship studies, binding model analysis and modes of action are highlighted. In particular, the unique multiple-copies binding mode of quinazoline derivatives paves new ways for the development of reversible LSD1 inhibitors by blocking the substrate entrance. The design strategy of clinical candidate TAK-418 also provides directions for further optimization of novel irreversible LSD1 inhibitors with low hematological side effects. The influence of the stereochemistry on the potency against LSD1 and its homolog LSD2 is briefly discussed. Finally, the challenges and prospects of LSD1-targeted drug discovery are also given. [ABSTRACT FROM AUTHOR]

Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) encoded by the proto-oncogene PTPN11 is the first identified non-receptor protein tyrosine phosphatase. SHP2 dysregulation contributes to the pathogenesis of different cancers, making SHP2 a promising therapeutic target for cancer therapy. In this article, we report the structure-guided design based on the well-characterized SHP2 inhibitor SHP099, extensive structure-activity relationship studies (SARs) of aminopyrazines, biochemical characterization and cellular potency. These medicinal chemistry efforts lead to the discovery of the lead compound TK-453 , which potently inhibits SHP2 (SHP2WT IC 50 = 0.023 μM, ΔTm = 7.01 °C) in a reversible and noncompetitive manner. TK-453 exhibits high selectivity over SHP2PTP, SHP1 and PTP1B, and may bind at the "tunnel" allosteric site of SHP2 as SHP099. As the key pharmacophore, the aminopyrazine scaffold not only reorganizes the cationic-π stacking interaction with R111 via the novel hydrogen bond interaction between the S atom of thioether linker and T219, but also mediates a hydrogen bond with E250. In vitro studies indicate that TK-453 inhibits proliferation of HeLa, KYSE-70 and THP-1 cells moderately and induces apoptosis of Hela cells. Further mechanistic studies suggest that TK-453 can decrease the phosphorylation levels of AKT and Erk1/2 in HeLa and KYSE-70 cells. Collectively, TK-453 is a highly potent, selective, and cellularly active allosteric SHP2 inhibitor that modulates the phosphorylation of SHP2-mediated AKT and Erk cell signaling pathways by inhibiting the phosphatase activity of SHP2. [Display omitted] • 48 aminopyrazine derivatives were synthesized and evaluated inhibitory activity against SHP2. • TK-453 is a highly potent, selective, and cellularly active allosteric SHP2 inhibitor. • TK-453 can modulate the phosphorylation of SHP2-mediated AKT and Erk cell signaling pathways. [ABSTRACT FROM AUTHOR]

Hydrothermal synthesis, Oxygen vacancy, Photocatalysis, Tin, Visible light Keywords: Hydrothermal synthesis; Oxygen vacancy; Photocatalysis; Tin; Visible light EN Hydrothermal synthesis Oxygen vacancy Photocatalysis Tin Visible light 4315 4315 1 11/18/21 20211115 NES 211115 B The Cover Feature b shows a tin oxide photocatalyst with strong visible light catalytic performance. Cover Feature: High Visible Light Photocatalytic Activity of SnO2-x Nanocrystals with Rich Oxygen Vacancy (Eur. J. Inorg. [Extracted from the article]