A comprehensive review of new small molecule drugs approved by the FDA in 2022: Advance and prospect.

In 2022, the U.S. Food and Drug Administration approved a total of 16 marketing applications for small molecule drugs, which not only provided dominant scaffolds but also introduced novel mechanisms of action and clinical indications. The successful cases provide valuable information for optimizing efficacy and enhancing pharmacokinetic properties through strategies like macrocyclization, bioequivalent group utilization, prodrug synthesis, and conformation restriction. Therefore, gaining an in-depth understanding of the design principles and strategies underlying these drugs will greatly facilitate the development of new therapeutic agents. This review focuses on the research and development process of these newly approved small molecule drugs including drug design, structural modification, and improvement of pharmacokinetic properties to inspire future research in this field.

The recent advance and prospect of poly(ADP-ribose) polymerase inhibitors for the treatment of cancer.

Chemotherapies are commonly used in cancer therapy, their applications are limited to low specificity, severe adverse reactions, and long-term medication-induced drug resistance. Poly(ADP-ribose) polymerase (PARP) inhibitors are a novel class of antitumor drugs developed to solve these intractable problems based on the mechanism of DNA damage repair, which have been widely applied in the treatment of ovarian cancer, breast cancer, and other cancers through inducing synthetic lethal effect and trapping PARP-DNA complex in BRCA gene mutated cancer cells. In recent years, PARP inhibitors have been widely used in combination with various first-line chemotherapy drugs, targeted drugs and immune checkpoint inhibitors to expand the scope of clinical application. However, the intricate mechanisms underlying the drug resistance to PARP inhibitors, including the restoration of homologous recombination, stabilization of DNA replication forks, overexpression of drug efflux protein, and epigenetic modifications pose great challenges and desirability in the development of novel PARP inhibitors. In this review, we will focus on the mechanism, structure-activity relationship, and multidrug resistance associated with the representative PARP inhibitors. Furthermore, we aim to provide insights into the development prospects and emerging trends to offer guidance for the clinical application and inspiration for the development of novel PARP inhibitors and degraders.

A comprehensive review of small molecule drugs approved by the FDA in 2023: Advances and prospects.

In 2023, the U.S. Food and Drug Administration has approved 55 novel medications, consisting of 17 biologics license applications and 38 new molecular entities. Although the biologics license applications including antibody and enzyme replacement therapy set a historical record, the new molecular entities comprising small molecule drugs, diagnostic agent, RNA interference therapy and biomacromolecular peptide still account for over 50 % of the newly approved medications. The novel and privileged scaffolds derived from drugs, active molecules and natural products are consistently associated with the discovery of new mechanisms, the expansion of clinical indications and the reduction of side effects. Moreover, the structural modifications based on the promising scaffolds can provide the clinical candidates with the improved biological activities, bypass the patent protection and greatly shorten the period of new drug discovery. Therefore, conducting an appraisal of drug approval experience and related information will expedite the identification of more potent drug molecules. In this review, we comprehensively summarized the pertinent information encompassing the clinical application, mechanism, elegant design and development processes of 28 small molecule drugs, and expected to provide the promising structural basis and design inspiration for pharmaceutical chemists.

Effects of gravel on the water infiltration process and hydraulic parameters of stony soil in the eastern foothills of Helan Mountain, China.

The investigation into the impact of gravel on water infiltration process and hydraulic parameters in stony soil could offer a theoretical basis to enhance water availability in rocky mountain area. A one-dimensional vertical infiltration experiment was used in this study. Six groups of gravel content of 0% (CK), 10% (W1), 20% (W2), 30% (W3), 40% (W4) and 50% (W5) were established to explore the changes in the wetting front, cumulative infiltration volume and infiltration rate. Then the accuracy of four infiltration models in simulating soil water infiltration processes was evaluated. Finally, Hydrus-1D was used to perform numerical inversion of the soil water content after infiltration. The findings revealed that: (1) When the infiltration time reached 300 min, the wetting front of the W1, W2, W3, W4 and W5 treatments was 11.00%, 17.00%, 32.25%, 38.75% and 54.50% lower than CK, the cumulative infiltration volume was 29.80%, 38.97%, 45.62%, 54.74% and 73.17% lower than CK, and the stable infiltration rate was 50.98%, 52.94%, 66.67%, 68.63% and 86.27% lower than CK. (2) The soil-water infiltration processes were accurately described by the Horton model, the coefficient of determination (R2) > 0.935. (3) The simulation results of Hydrus-1D showed that with the increase of gravel content, the values of the retention water content (θr), saturated water content (θs), shape coefficient (n) and saturated hydraulic conductivity (Ks) were decreased, the values of the reciprocal of air-entry (α) were increased. The value of R2 was more than 0.894, the root mean square error (RMSE) and mean absolute error (MAE) were less than 2%, which demonstrated that the Hydrus-1D model exhibited superior capability in simulating the changes of water content in stony soil in rocky mountain area. The findings of this study demonstrated that gravel could decrease the water infiltration process and affect the water availability. It could provide data support for the water movement process of stony soil and rational utilization of limited water resources in mountainous area.

[Effect of Biochar on NO3--N Transport in Loessial Soil and Its Simulation].

The objective of this study was to explore the effects of different amounts of biochar on the migration process and characteristics of NO3--N in loessial soil. In this study, six groups of mixed soil samples with biochar and loessial soil mass ratios of 0% (T0), 1% (T1), 2% (T2), 3% (T3), 4% (T4), and 5% (T5) were used as research objects. NO3--N was used as the tracer. Through the indoor soil column solute transport simulation tests, the effects of different biochar application amounts on the NO3--N transport process in loessial soil were simulated and studied. The results showed that the breakthrough curve of NO3--N in loessial soil shifted to the right with the increasing of biochar application, and the peak value gradually decreased. The initial penetration time, complete penetration time, and total penetration time increased with the increasing of biochar application amount. The total penetration time of NO3- in the T1, T2, T3, T4, and T5 treatments was 1.26, 2.31, 2.72, 3.22, and 3.57 times that of T0, respectively. The R2 was > 0.997 and RMSE was < 2.083 of the two-zone model (TRM). Compared with the convection-dispersion equation (CDE), the TRM model had higher fitting accuracy and could better simulate the NO3--N migration process in loessial soil after the application of different contents of biochar. The analysis of the fitting parameters of the TRM model showed that the average pore velocity, hydrodynamic dispersion coefficient, and water content ratio in the movable zone gradually decreased with the increasing of biochar application, whereas the dispersion and mass exchange coefficient showed an increasing trend. The results showed that biochar application could effectively enhance the ability of loessial soil to fix NO3--N, reduce the leakage of NO3--N to groundwater, and play an important role in maintaining soil fertility and preventing groundwater pollution.

Recent advances of Pin1 inhibitors as potential anticancer agents.

Pin1 (proline isomerase peptidyl-prolyl isomerase NIMA-interacting-1), as a member of PPIase family, catalyzes cis-trans isomerization of pThr/Ser-Pro amide bonds of its substrate proteins, further regulating cell proliferation, division, apoptosis, and transformation. Pin1 is overexpressed in various cancers and is positively correlated with tumor initiation and progression. Pin1 inhibition can effectively reduce tumor growth and cancer stem cell expansion, block metastatic spread, and restore chemosensitivity, suggesting that targeting Pin1 may be an effective strategy for cancer treatment. Considering the promising therapeutic effects of Pin1 inhibitors on cancers, we herein are intended to comprehensively summarize the reported Pin1 inhibitors, mainly highlighting their structures, biological functions and binding modes, in hope of providing a reference for the future drug discovery.

Annual review of PROTAC degraders as anticancer agents in 2022.

Following nearly two decades of development, significant advancements have been achieved in PROTAC technology. As of the end of 2022, more than 20 drugs have entered clinical trials, with ARV-471 targeting estrogen receptor (ER) showing remarkable progress by entering phase III clinical studies. In 2022, significant progress has been made on multiple targets. The first reversible covalent degrader designed to target the KRASG12C mutant protein, based on cyclopropionamide, has been reported. Additionally, the activity HDCA1 degrader surpassed submicromolar levels during the same year. A novel FEM1B covalent ligand called EN106 was also discovered, expanding the range of available ligands. Furthermore, the first PROTAC drug targeting SOS1 was reported. Additionally, the first-in-class degraders that specifically target BRD4 isoforms (BRD4 L and BRD4 S) have recently been reported, providing a valuable tool for further investigating the biological functions of these isoforms. Lastly, a breakthrough was also achieved with the first degrader targeting both CDK9 and Cyclin T1. In this review, we aimed to update the PROTAC degraders as potential anticancer agents covering articles published in 2022. The design strategies, degradation effects, and anticancer activities were highlighted, which might provide an updated sight to develop novel PROTAC degraders with great potential as anticancer agents as well as favorable drug-like properties.

The recent advance of Interleukin-1 receptor associated kinase 4 inhibitors for the treatment of inflammation and related diseases.

The interleukin-1 receptor associated kinase 4 (IRAK-4) is a member of serine-threonine kinase family, which plays an important role in the regulation of interleukin-1 receptors (IL-1R) and Toll-like receptors (TLRs) related signaling pathways. At present, the IRAK-4 mediated inflammation and related signaling pathways contribute to inflammation, which are also responsible for other autoimmune diseases and drug resistance in cancers. Therefore, targeting IRAK-4 to develop single-target, multi-target inhibitors and proteolysis-targeting chimera (PROTAC) degraders is an important direction for the treatment of inflammation and related diseases. Moreover, insight into the mechanism of action and structural optimization of the reported IRAK-4 inhibitors will provide the new direction to enrich the clinical therapies for inflammation and related diseases. In this comprehensive review, we introduced the recent advance of IRAK-4 inhibitors and degraders with regards to structural optimization, mechanism of action and clinical application that would be helpful for the development of more potent chemical entities against IRAK-4.

Oxazolidinone: A promising scaffold for the development of antibacterial drugs.

Due to the long-term and widespread use of antibiotics in clinic, the problem of bacterial resistance is increasingly serious, and the development of new drugs to treat drug-resistant bacteria has gradually become the mainstream direction of antibiotic research. The oxazolidinone-containing drugs linezolid, tedizolid phosphate and contezolid have been approved to the market, which are effective against a variety of Gram-positive bacterium infections. Moreover, there are also many antibiotics containing oxazolidinone fragment under clinical investigation that show good pharmacokinetic and pharmacodynamic properties with unique mechanism of action against resistant bacteria. In this review, we summarized the oxazolidinone-based antibiotics already on the market or in clinical trials and the representative bioactive molecules, and mainly focused on their structural optimizations, development strategies and structure-activity relationships in hope of insight into the reasonable design for medical chemists to develop new oxazolidinone antibiotics with highly potency and fewer side effects.

[Spatial Distribution and Source Analysis of Soil Heavy Metals in a Small Watershed in the Mountainous Area of Southern Ningxia Based on PMF Model].

In order to ascertain the distribution characteristics of soil heavy metal pollution and main pollution sources in a small watershed in the southern mountainous area of Ningxia and to ensure the quality of the soil environment, the contents of heavy metals Pb, Ni, Zn, Mn, Cu, Cr, and Cd in 260 surface soil samples (0-20 cm) were collected and determined. Based on the soil background value in Ningxia, the soil heavy metal pollution status and potential ecological risk were evaluated through the single factor index, Nemera composite index, and potential ecological risk index, and the method of combining positive definite matrix factor analysis (PMF) and Kriging interpolation was used to analyze the soil heavy metal spatial distribution and source. The results showed that the average contents of ω(Pb), ω(Ni), ω(Zn), ω(Mn), ω(Cu), ω(Cr), and ω(Cd) were 31.42, 36.22, 62.89, 546.18, 22.26, 61.90, and 0.18 mg·kg-1, respectively. Except for Ni, the other elements were higher than the background value of Ningxia but lower than the background value of agricultural soil pollution risk selection criteria and green food environmental quality standards. The Nemera composite index showed that the proportions of mild, moderate, and severe heavy metal pollution were 71.92%, 19.23%, and 1.54%, respectively. The potential ecological risks were mainly minor risks, accounting for 98.85%. In addition, there were a very small number of samples with medium potential ecological risk levels, accounting for 1.15% of the total number of samples. Source analysis showed that the main sources of soil heavy metals in the small watershed in the mountainous area of southern Ningxia were mixed sources of fertilization and industrial emissions (12.6%), agricultural activity sources (23.5%), natural parent material sources (27.6%), mixed sources of pesticide use and mining development emissions (17.7%), and atmospheric deposition sources (18.6%).

[Spatial Distribution Characteristics, Source Apportionment, and Risk Assessment of Topsoil PAHs in the Core Area of the Ningdong Energy and Chemical Industry Base].

In order to evaluate the pollution of polycyclic aromatic hydrocarbons (PAHs) in the topsoil of the core area of the Ningdong Energy and Chemical Industry Base, 146 representative topsoil samples were collected using the grid method and the contents of 16 priority PAHs were analyzed. The results showed that the content of ΣPAHs in topsoil ranged from ND to 123.12 mg·kg-1 with an average of 10.19 mg·kg-1. There were three high PAHs distribution areas in the northwest, southwest, and east of the core area. The source apportionment showed that the sources of PAHs in the Ningdong base were complex, and the main pollution sources were petroleum, coal combustion, traffic, and gasoline, which contributed 39.4%, 33.3%, 19.2%, and 8.1% to the total PAHs sources, respectively. The ecological risk assessment of the quality basis and quality standard method showed that the ecological impact of PAHs in the core area was slight and the possibility of negative ecological effects was low. The results of the health risk assessment showed that the order of exposure of the topsoil PAHs was skin contact > swallowing > respiratory inhalation, and the topsoil PAHs in the core area of the Ningdong base posed no potential carcinogenic risk to people of different ages.

[Spatial Distribution Characteristics and Source Apportionment of Soil PAHs in Shizuishan City Based on GIS and PMF Model].

With the acceleration of urbanization and industrialization, the content and pollution of polycyclic aromatic hydrocarbons (PAHs) in urban soils have been sources of widespread concern. Taking Shizuishan City as an example, the spatial distribution characteristics of PAHs in 156 surface soil samples (0-20 cm) from eight urban functional areas were analyzed. Single factor and Nemero composite indices, as well as a lifetime cancer risk increment model were used to evaluate PAHs pollution in soils. The sources of PAHs were analyzed using the positive matrix factorization (PMF) model. The results showed that the mean value of PAHs in the surface soil of Shizuishan City was 489.82 ng·g-1 and the coefficient of variation of 15 PAHs except for Pyr were more than 100%, indicating strong variation. The PAH contents of urban surface soils in different functional areas showed the following:traffic area (1217.61 ng·g-1) > industrial area (809.58 ng·g-1) > park (273.66 ng·g-1) > cultural and educational area (268.18 ng·g-1) > commercial area (240.05 ng·g-1) > agricultural area (226.81 ng·g-1) > medical area (211.90 ng·g-1) > residential area (183.49 ng·g-1). The Nemero composite index showed that 82.58% of the samples had no pollution, and the proportion of slight, mild, and moderate pollution were 6.45%, 4.52%, and 0.65%, respectively. Only 5.8% of the samples had serious pollution. The results of health risk assessment showed that skin contact and ingestion were the main routes of PAH exposure in soil, and the health risk was acceptable. Source analysis showed that the main sources of PAHs in Shizuishan City were traffic emissions, coal combustion, mixed biomass/heavy oil combustion, and oil sources, with contribution rates of 10.5%, 36.6%, 50.3%, and 2.6% respectively, and most of the high values were distributed in industrial or coal production areas. These results could provide reference for the study of soil pollution in industrial cities, and play an important role in preventing soil pollution, ensuring the environmental quality of the soil and human health and safety.

Inhibition of autophagy improves resistance and enhances sensitivity of gastric cancer cells to cisplatin.

Autophagy plays critical roles in tumorigenesis, while the effects of autophagy on chemoresistance of cancer cells had great disparity. This study aims to explore the impacts of autophagy on the sensitivity and resistance of gastric cancer cells to cisplatin (DDP). We firstly demonstrated that there was stronger autophagy activity in gastric cancer SGC-7901 cells than that in DDP-resisting SGC-7901/DDP cells. Then, we discovered that inhibiting autophagy by chloroquine (CQ) significantly enhanced the proliferation-inhibiting and apoptosis-inducing effects of DDP to SGC-7901 and SGC-7901/DDP cells. Moreover, CQ could partially reverse the resistance of SGC-7901/DDP cells to DDP in a concentration-dependent manner. However, the autophagy inducer everolimus (RAD001) had no obvious effects on the sensitivity of gastric cells to DDP. Mechanistically, we demonstrated that CQ might enhance the sensitivity of SGC-7901cells and improve the resistance of SGC-7901/DDP cells to DDP through inhibiting the mTORC1 pathway, especially to SGC-7901/DDP cells. Additionally, we found interfering Beclin-1 using Beclin-1 shRNA also enhanced the proliferation-inhibiting and apoptosis-inducing effects of DDP on gastric cancer cells by inhibiting phosphorylation of Akt. Our study shows that inhibiting autophagy could improve the chemoresistance and enhanced sensitivity of gastric cancer cells to DDP and provide a rationale for the administration of cisplatin combined with CQ for treating patients with gastric cancer.

[Spatial Distribution Characteristics and Source Apportionment of Soil Heavy Metals in Chinese Wolfberry Land Based on GIS and the Receptor Model].

A total of 119 surface soil samples (depth of 0-20 cm) were collected from a Chinese wolfberry demonstration garden in Zhongning of Ningxia, and samples were analyzed for seven heavy metals (Pb, Ni, Zn, Mn, Cu, Cr, and Cd). The single factor index, comprehensive index, and potential ecological risk were used to assess the soil heavy metal contamination with the soil background values of Ningxia as the evaluation standards. The absolute principal component scores and multivariate linear regression (APCS-MLR) model as well as geostatistic analysis were combined to identify and apportion the pollution sources of soil heavy metals. The results showed that the average concentrations of Pb, Ni, Zn, Mn, Cu, Cr, and Cd in soils were 34.78, 52.376, 83.692, 641.114, 38.130, 87.257, and 0.149 mg·kg-1, respectively. The mean concentrations of heavy metals were higher than the local soil background values but lower than the risk screening values for soil contamination of agricultural land. The comprehensive index results showed that the pollution degree of soil heavy metals was at the slightly polluted level in 81.51% of the samples, at the moderately polluted level in 16.81% of the samples, and at the unpolluted level in 1.68% of the samples. The comprehensive index values for potential ecological hazards were less than 60 in 13.45% of the samples, and these values were associated with a slight potential for ecological risks. The comprehensive index values for potential ecological hazards were less than 120 and more than 60 in 86.55% of the samples, and these values were associated with a moderate potential for ecological risks. The four main pollution sources of soil heavy metals in the study area included natural sources, industrial activity, traffic, and agricultural activity. Natural sources were the main source of Ni and Cr with average contribution rates of 55.49% and 64.66%, respectively. Industrial activity was the main source of Pb and Mn with average contribution rates of 46.93% and 42.53%, respectively. Traffic was the main source of Zn and Cu with average contribution rates of 43.51% and 53.71%, respectively. Agricultural activity was the main source of Cd with an average contribution rate of 76.79%. The study results indicated that soil heavy metals have tended to concentrate in the Chinese wolfberry demonstration garden, and the sources of heavy metals were complex and obviously influenced by human activities. Controls should be strengthened for sources that contribute to soil heavy metals to ensure the sustainable utilization of soil resources in the Chinese wolfberry land.

[Spatial Heterogeneity of Soil Carbon and its Fractions in the Wolfberry Field of Zhongning County].

It is important to accurately assess the regional spatial distribution and variation of soil carbon and its fractions due to its great significance in soil carbon cycling and soil quality. The objectives of this study were to investigate the spatial variability of soil carbon and its fractions using classical and geostatistical statistics. Topsoil samples (0-20 cm) from 119 sites in Wolfberry Field were collected from a grid of 100 m×100 m in Zhongning County. The GS+7.0 software was used to fit a semivariance model to determine the optimal theoretical model and parameters. The spatial distribution characteristics of soil carbon and its fractions were studied by ordinary kriging. The classical statistical analyses showed that the average concentrations of total carbon, inorganic carbon, organic carbon, active organic carbon, medium active organic carbon, and high active organic carbon were 28.74, 18.72, 10.09, 1.81, 1.48, and 0.73 g·kg-1, respectively. The variation coefficient of total carbon and inorganic carbon were 7.69% and 9.13%, indicating a strong variation, while the other soil carbon fractions showed moderate variation with the coefficients of variations ranging from 14.77%-52.05%. The geostatistical analyses revealed that the semivariogram of organic carbon was best fit by the spherical model, while the other five kinds of carbon fractions were best fit by the exponential model. The nugget coefficients of total carbon and organic carbon were 48.99% and 34.35%, which demonstrated moderate spatial dependence. The nugget coefficients of inorganic carbon, active organic carbon, medium active organic carbon, and high active organic carbon were 8.17%, 0.25%, 12.18%, and 0.08%, which demonstrated strong spatial dependence. The ordinary kriging interpolation map indicated that the spatial distribution patterns were similar for total carbon, organic carbon, medium active organic carbon, and high active organic carbon, which increased from southeast to northwest. Inorganic carbon and active organic carbon presented an irregular plaque distribution in the study area. Spatial interpolation maps could provide useful information for environmental management and the sustainable use of land resources in this region.

[Distribution of Urban Soil Heavy Metal and Pollution Evaluation in Different Functional Zones of Yinchuan City].

Surface soil samples (0-20 cm) from eight different functional areas in Yinchuan city were collected. There were 10 samples respectively in each functional area. The urban soil heavy metals (Zn, Cd, Pb, Mn, Cu and Cr) pollution characteristics and sources in eight different functional areas were evaluated by mathematical statistics and geostatistical analysis method. Meanwhile, the spatial distributions of heavy metals based on the geography information system (GIS) were plotted. The average values of total Zn, Cd, Pb, Mn, Cu and Cr were 74.87, 0.15, 29.02, 553.55, 40.37 and 80.79 mg x kg(-1), respectively. The results showed that the average value of soil heavy metals was higher than the soil background value of Ningxia, which indicated accumulation of the heavy metals in urban soil. The single factor pollution index of soil heavy metals was in the sequence of Cu > Pb > Zn > Cr > Cd > Mn. The average values of total Zn, Cd, Pb and Cr were higher in north east, south west and central city, while the average values of Mn and Cu were higher in north east and central city. There was moderate pollution in road and industrial area of Yinchuan, while the other functional areas showed slight pollution according to Nemoro synthesis index. The pollution degree of different functional areas was as follows: road > industrial area > business district > medical treatment area > residential area > public park > development zone > science and education area. The results indicated that the soil heavy metal pollution condition in Yinchuan City has been affected by human activities with the development of economy.

[Distribution of soil heavy metal and pollution evaluation on the different sampling scales in farmland on Yellow River irrigation area of Ningxia: a case study in Xingqing County of Yinchuan City].

Determining spatial distributions and analyses contamination condition of soil heavy metals play an important role in evaluation of the quality of agricultural ecological environment and the protection of food safety and human health. Topsoil samples (0-20 cm) from 223 sites in farmland were collected at two scales of sampling grid (1 m x 1 m, 10 m x 10 m) in the Yellow River irrigation area of Ningxia. The objectives of this study were to investigate the spatial variability of total copper (Cu), total zinc (Zn), total chrome (Cr), total cadmium (Cd) and total lead (Pb) on the two sampling scales by the classical and geostatistical analyses. The single pollution index (P(i)) and the Nemerow pollution index (P) were used to evaluate the soil heavy metal pollution. The classical statistical analyses showed that all soil heavy metals demonstrated moderate variability, the coefficient of variation (CV) changed in the following sequence: Cd > Pb > Cr > Zn > Cu. Geostatistical analyses showed that the nugget coefficient of Cd on the 10 m x 10 m scale and Pb on the 1 m x 1 m scale were 100% with pure nugget variograms, which showed weak variability affected by random factors. The nugget coefficient of the other indexes was less than 25%, which showed a strong variability affected by structural factors. The results combined with P(i) and P indicated that most soil heavy metals have slight pollution except total copper, and in general there were the trend of heavy metal accumulation in the study area.