Natural Amino Acid-Bearing Carbamate Prodrugs of Daidzein Increase Water Solubility and Improve Phase II Metabolic Stability for Enhanced Oral Bioavailability.

Daidzein (DAN) is an isoflavone, and it is often found in its natural form in soybean and food supplements. DAN has poor bioavailability owing to its extremely low water solubility and first-pass metabolism. Herein, we hypothesized that a bioactivatable natural amino acid-bearing carbamate prodrug strategy could increase the water solubility and metabolic stability of DAN. To test our hypothesis, nine amino acid prodrugs of DAN were designed and synthesized. Compared with DAN, the optimal prodrug (daidzein-4'-O-CO-N-isoleucine, D-4'-I) demonstrated enhanced water solubility and improved phase II metabolic stability and activation to DAN in plasma. In addition, unlike the passive transport of DAN, D-4'-I maintained high permeability via organic anion-transporting polypeptide 2B1 (OATP2B1)-mediated transport. Importantly, D-4'-I increased the oral bioavailability by 15.5-fold, reduced the gender difference, and extended the linear absorption capacity in the pharmacokinetics of DAN in rats. Furthermore, D-4'-I exhibited dose-dependent protection against liver injury. Thus, the natural amino acid-bearing carbamate prodrug strategy shows potential in increasing water solubility and improving phase II metabolic stability to enhance the oral bioavailability of DAN.

MicroRNA-599-Regulated Susceptibility to Acute Kidney Injury in Patients with Cirrhosis is Mediated by the Sirtuin 1 (SIRT1) rs4746720 Single Nucleotide Polymorphism.

OBJECTIVE: The aim of this case-control study was to analyze the association between sirtuin 1 (SIRT1) single nucleotide polymorphism (SNP) and the risk of acute kidney injury (AKI) in Han Chinese patients with cirrhosis and to explore its potential mechanism. METHODS: Twenty-nine AKI patients with cirrhosis (AKI group) and 87 non-AKI patients with cirrhosis (control group) were recruited from a Han Chinese population. SNaPshot sequencing technology was used for the detection of SNPs. Dual luciferase reporter vectors were constructed and co-transfected into HK-2 human proximal tubular epithelial cells. SIRT1-overexpressing recombinant plasmids were constructed and co-transfected into HK-2 cells. The expression of microRNA-599 (miR-599) and SIRT1/peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α)/nuclear respiratory factor 1 (NRF1)/mitochondrial transcription factor A (TFAM) was detected by the quantitative polymerase chain reaction, and the expression of the corresponding proteins was detected by Western blotting. RESULTS: There were no statistically significant between-group differences in the genotype and allele frequencies of SIRT1 rs4746720. In the subgroup of patients with hepatic encephalopathy, the SIRT1 rs4746720 SNP was significantly associated with the development of AKI, and the risk of AKI in patients with the T allele was six times higher than in those with the C allele. The results of the in vitro experiments demonstrated that the T allele of SIRT1 rs4746720 increased the binding of miR-599 to the rs4746720 locus within the 3'-UTR of SIRT1 (p < 0.001). The results of the SIRT1-overexpressing recombinant plasmid experiments confirmed that the T allele of SIRT1 rs4746720 mediated the binding of miR-599, leading to decreased SIRT1 and PGC-1α, NRF1, and TFAM (p < 0.05). CONCLUSIONS: The SIRT1 rs4746720 SNP might be linked with AKI in cirrhotic patients, and the T allele increased the risk of AKI in those with hepatic encephalopathy. The rs4746720 SNP in the SIRT1 3'-UTR is linked to the development of AKI in cirrhotic patients with hepatic encephalopathy, potentially by mediating the binding of miR-599.

Shear mechanical response and deformation failure of F-type socket joint in a rectangular pipe jacking tunnel under different geologic conditions.

The shear mechanical properties of F-type socket joints in rectangular pipe jacking tunnels are currently unknown. To investigate the shear mechanical response and deformation failure of the F-type socket joint in rectangular pipe jacking tunnels under different foundation coefficients, a laboratory joint test and numerical simulation method were used, considering the structural features of the joint. The results showed that the deformation process of a joint subjected to shear consists of four stages: gap closure, elastic growth, shear strengthening, and yield failure. The ultimate shear capacity of the joint increases by 25% to 34% for every 3 mm increase in the steel ring thickness. The chamfer yield damage area comprises approximately 15% of the steel ring. The joint concrete crack first appears at the top of the socket joint, and the concrete damage area accounts for about 40% of the whole pipe section. The failure characteristics of the joint are primarily manifested as drum and warp of the steel ring or cracking of the weld, and the concrete at the joint is crushed. In practical engineering, the weld should not be located at the chamfer. The steel ring at the chamfer needs to be locally strengthened, and the chamfer and the reinforcement at the top and bottom need to be increased to improve the bearing capacity of the concrete.

Factors influencing the healthcare transition in Chinese adolescents with inflammatory bowel disease: a multi-perspective qualitative study.

BACKGROUND: The development and implementation of the transition from pediatric to adult healthcare systems for adolescents with inflammatory bowel disease (IBD) should consider stakeholders' perceptions. This study aimed to explore the factors influencing the transition of Chinese adolescents with IBD from the perspectives of patients, parents, and healthcare providers. METHODS: A descriptive qualitative research was conducted. Purposive sampling was used to recruit 36 participants, including 13 patients, 13 parents, and 10 providers, from a tertiary pediatric IBD center, a tertiary adult IBD center, and the China Crohn's & Colitis Foundation in Zhejiang Province, China. Individual semi-structured interviews were used to collect data on facilitators and barriers to the transition process. Conventional content analysis was used to analyze the interview transcripts. RESULTS: Nine primary themes were identified. Patients with young age, prolonged disease duration, severe disease, academic pressures such as the Gaokao, low level of disease acceptance, limited transition consciousness, low self-efficacy, poor transition communication, and inadequate medical transition system serve as barriers. While patients with the mentality of guilt towards their parents; parents with low education levels and intensive work schedules, high levels of disease acceptance, and situations of parent-child separation; stakeholders with high transition consciousness, high transition self-efficacy, and effective transition communication act as facilitators. Furthermore, community support and hospital guide services were also contributing factors during the transition. CONCLUSIONS: This study offers comprehensive insights into the factors affecting the transition of Chinese adolescent IBD patients. The process is continuously influenced by stakeholders, community, and healthcare environments and policies. Identifying these factors provides healthcare providers with a reference for developing and implementing targeted transition interventions.

Correlation between neutrophil-to-lymphocyte ratio and contrast-induced acute kidney injury and the establishment of machine-learning-based predictive models.

OBJECTIVE: To explore the correlation between neutrophil-to-lymphocyte ratio (NLR) and contrast-induced acute kidney injury (CI-AKI). To develop machine-learning (ML) methods based on NLR and other relevant high-risk factors to establish new and effective predictive models of CI-AKI. Methods: The data of 2230 patients, who underwent elective vascular intervention, coronary angiography and percutaneous coronary intervention were retrospectively collected. The patients were divided into a CI-AKI group and a non-CI-AKI group. Logistic regression was used to analyze the correlation of NLR with CI-AKI and high-risk factors for CI-AKI, and logistic regression (LR), random forest (RF), gradient boosting decision tree (GBDT), extreme gradient boosting (XGBoost), and naïve Bayes (NB) models based on NLR and the high-risk factors were established. RESULTS: A high NLR(>2.844) was an independent risk factor for CI-AKI (odds ratio = 2.304, p < 0.001). The area under the ROC curve (AUC) of the NB model was the largest (0.774), indicating that it had the best performance. NLR, serum creatinine concentration, fasting plasma glucose concentration, and use of ß-blocker all accounted for a large proportion of the predictive performance of each model and were the four most important factors affecting the occurrence of CI-AKI. CONCLUSIONS: There was a significant correlation between NLR and CI-AKI The NB model exhibited the best predictive performance out of the five ML models based on NLR exhibited the best predictive performance out of the five ML models.

A Mechanism Study on the (+)-ESI-TOF/HRMS Fragmentation of Some PPI Prazoles and Their Related Substances.

Fragmentation mechanisms of some prazoles and their related substances were newly investigated in this paper via positive mode ESI-TOF HRMS1 and HRMS2. Some novel fragmentation rules or ions were found or detected in the research. The pyridine and the benzoimidazole ring remained in most cases during the ionization, and heterolytic fragmentations often occurred near the -S(O)nCH2- linker to give the [1,3]-H migration ion or [1,7]-H migration ion rearranging across the benzoimdazole ring. Smiles rearrangement ionizations also frequently occurred, initiated by the attack of the lone pair electrons from the pyridine ring, and the sulfones gave special N-(2-benzoimdazolyl) pyridine ions (11b and 12c) by a direct extraction from SO2, and the thioethers gave similar framework ions (8c, 9c and 10c) via the rearrangement and a further homolytic cleavage of SH radicals. However, the sulfoxides were seldom detected in the corresponding Smiles rearrangement ions during our measurement, and the N'-oxides of the pyridines did not undergo the Smiles rearrangement ionization due to the absence of the lone pair electrons. The 5/6-membered chelating ions with Na+ or K+ were frequently detected as the molecular and further fragment ions. Some novel and interesting fragment ions containing bivalent (8b and 9b), tetravalent (4b, 5c and 6c) or hexavalent (15b and 16b) sulfurs were first reported here.

Design, Synthesis, and Biological Evaluation of Sulfonamide Methoxypyridine Derivatives as Novel PI3K/mTOR Dual Inhibitors.

Phosphatidylinositol 3-kinase (PI3K) plays an important role in cell proliferation, survival, migration, and metabolism, and has become an effective target for cancer treatment. Meanwhile, inhibiting both PI3K and mammalian rapamycin receptor (mTOR) can simultaneously improve the efficiency of anti-tumor therapy. Herein, a series of 36 sulfonamide methoxypyridine derivatives with three different aromatic skeletons were synthesized as novel potent PI3K/mTOR dual inhibitors based on a scaffold hopping strategy. Enzyme inhibition assay and cell anti-proliferation assay were employed to assess all derivatives. Then, the effects of the most potent inhibitor on cell cycle and apoptosis were performed. Furthermore, the phosphorylation level of AKT, an important downstream effector of PI3K, was evaluated by Western blot assay. Finally, molecular docking was used to confirm the binding mode with PI3Kα and mTOR. Among them, 22c with the quinoline core showed strong PI3Kα kinase inhibitory activity (IC50 = 0.22 nM) and mTOR kinase inhibitory activity (IC50 = 23 nM). 22c also showed a strong proliferation inhibitory activity, both in MCF-7 cells (IC50 = 130 nM) and HCT-116 cells (IC50 = 20 nM). 22c could effectively cause cell cycle arrest in G0/G1 phase and induce apoptosis of HCT-116 cells. Western blot assay showed that 22c could decrease the phosphorylation of AKT at a low concentration. The results of the modeling docking study also confirmed the binding mode of 22c with PI3Kα and mTOR. Hence, 22c is a promising PI3K/mTOR dual inhibitor, which is worthy of further research in the area.

QuoteTarget: A sequence-based transformer protein language model to identify potentially druggable protein targets.

The development of efficient computational methods for drug target protein identification can compensate for the high cost of experiments and is therefore of great significance for drug development. However, existing structure-based drug target protein-identification algorithms are limited by the insufficient number of proteins with experimentally resolved structures. Moreover, sequence-based algorithms cannot effectively extract information from protein sequences and thus display insufficient accuracy. Here, we combined the sequence-based self-supervised pretraining protein language model ESM1b with a graph convolutional neural network classifier to develop an improved, sequence-based drug target protein identification method. This complete model, named QuoteTarget, efficiently encodes proteins based on sequence information alone and achieves an accuracy of 95% with the nonredundant drug target and nondrug target datasets constructed for this study. When applied to all proteins from Homo sapiens, QuoteTarget identified 1213 potential undeveloped drug target proteins. We further inferred residue-binding weights from the well-trained network using the gradient-weighted class activation mapping (Grad-Cam) algorithm. Notably, we found that without any binding site information input, significant residues inferred by the model closely match the experimentally confirmed drug molecule-binding sites. Thus, our work provides a highly effective sequence-based identifier for drug target proteins, as well to yield new insights into recognizing drug molecule-binding sites. The entire model is available at https://github.com/Chenjxjx/drug-target-prediction.

The Incidence, Risk Factors, and Outcomes of Acute Kidney Injury in Patients with Decompensated Cirrhosis: A Retrospective Study.

BACKGROUND: To evaluate the incidence, risk factors, and outcomes of acute kidney injury (AKI) in patients with decompensated cirrhosis based on the Kidney Disease: Improving Global Outcomes Clinical Practice Guideline. METHODS: For this retrospective analysis, 923 inpatients were recruited between January 2013 and December 2017. The patients' baseline demographics and clinical information were collected and analyzed. Univariate and multiple logistic regression analyses were conducted to determine the independent risk factors for AKI and in-hospital mortality. Kaplan-Meier survival analyses were used to analyze the between-group differences in mortality. RESULTS: Of the 923 patients, 262 (28.39%) developed AKI. According to the multivariate analysis, an age ≥65 years (odds ratio [OR]: 1.776, 95% confidence interval [CI]: 1.288-2.449, p < 0.001), infection (OR: 1.386, 95% CI: 1.024-1.875, p = 0.034), hypotension (OR: 1.709, 95% CI: 1.091-2.679, p = 0.019), white blood cell count >10 × 109 /L (OR: 4.054, 95% CI: 2.006-8.193, p < 0.001), albumin concentration <35 g/L (OR: 1.931, 95% CI: 1.392-2.680, p < 0.001), baseline serum creatinine concentration >88.4 µmol/L (OR: 2.136, 95% CI: 1.511-3.021, p < 0.001), estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 (OR: 2.384, 95% CI: 1.372-4.145, p = 0.002), and serum sodium concentration <135 mmol/L (OR: 1.686, 95% CI: 1.155-2.459, p = 0.007) were independent risk factors for AKI. Moreover, AKI was significantly associated with in-hospital mortality (OR: 6.934, 95% CI: 1.333-11.052, p = 0.021). Kaplan-Meier survival analysis confirmed that patients with AKI had higher in-hospital mortality than those without AKI. CONCLUSIONS: The incidence of AKI was high among patients with decompensated cirrhosis. Infection, an elevated baseline serum creatinine concentration, and decreased eGFR were independent risk factors for both AKI and in-hospital mortality. AKI was an independent risk factor for in-hospital mortality. Based on the risk factors identified, AKI prediction models and treatment approaches care bundles can be used for the early identification and modification of potential predisposing factors and for improving outcomes in these patients in the future.

The Incidence, Risk Factors, and Outcomes of Acute Kidney Injury in Patients with Decompensated Cirrhosis: A Retrospective Study

Background: To evaluate the incidence, risk factors, and outcomes of acute kidney injury (AKI) in patients with decompensated cirrhosis based on the Kidney Disease: Improving Global Outcomes Clinical Practice Guideline. Methods: For this retrospective analysis, 923 inpatients were recruited between January 2013 and December 2017. The patients’ baseline demographics and clinical information were collected and analyzed. Univariate and multiple logistic regression analyses were conducted to determine the independent risk factors for AKI and in-hospital mortality. Kaplan–Meier survival analyses were used to analyze the between-group differences in mortality. Results: Of the 923 patients, 262 (28.39%) developed AKI. According to the multivariate analysis, an age ≥65 years (odds ratio [OR]: 1.776, 95% confidence interval [CI]: 1.288–2.449, p < 0.001), infection (OR: 1.386, 95% CI: 1.024–1.875, p = 0.034), hypotension (OR: 1.709, 95% CI: 1.091–2.679, p = 0.019), white blood cell count >10 × 109 /L (OR: 4.054, 95% CI: 2.006–8.193, p < 0.001), albumin concentration <35 g/L (OR: 1.931, 95% CI: 1.392–2.680, p < 0.001), baseline serum creatinine concentration >88.4 µmol/L (OR: 2.136, 95% CI: 1.511–3.021, p < 0.001), estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 (OR: 2.384, 95% CI: 1.372–4.145, p = 0.002), and serum sodium concentration <135 mmol/L (OR: 1.686, 95% CI: 1.155–2.459, p = 0.007) were independent risk factors for AKI. Moreover, AKI was significantly associated with in-hospital mortality (OR: 6.934, 95% CI: 1.333–11.052, p = 0.021). Kaplan–Meier survival analysis confirmed that patients with AKI had higher in-hospital mortality than those without AKI. Conclusions: The incidence of AKI was high among patients with decompensated cirrhosis (AU)

Design, synthesis, and biological evaluation of 2-arylamino-4-(piperidin-4-yloxy)pyrimidines as potent EGFRT790M/L858R inhibitors to treat non-small cell lung cancer.

Three types of 2-arylamino-4-(piperidin-4-yloxy)pyrimidines (I-III) were designed and synthesized as covalent EGFR(epidermal growth factor receptor)T790M/L858R inhibitors by replacement of the common reported 4-(3-amino)phenoxyl moiety with 4-(4-hydroxy)piperidine-4-oxyl, and the introduction of fused-thiophene or -pyrrole on the pyrimidine core to strategically achieve conformational restriction. According to our biological evaluation, it was found that compound 9i could potently suppress EGFRT790M/L858R kinase and H1975 cell proliferation, with IC50 values of 4.902 nM and 0.6210 µM, respectively. Further study showed that 9i not only demonstrated highly selective inhibitory effects toward EGFRT790M/L858R over wild-type EGFR (EGFRWT), but it also had low cytotoxicity against normal HBE(human bronchial epithelial) and L-02 cells. Action mechanism studies showed that 9i effectively hindered cell migration and promoted apoptosis by AO(Acridine Orange)/EB(Ethidium Bromide) staining. These data would provide important clues for the screening of novel covalent EGFRT790M/L858R inhibitors for non-small cell lung cancer (NSCLC) treatment.

MolMiner: You Only Look Once for Chemical Structure Recognition.

Molecular structures are commonly depicted in 2D printed forms in scientific documents such as journal papers and patents. However, these 2D depictions are not machine readable. Due to a backlog of decades and an increasing amount of printed literatures, there is a high demand for translating printed depictions into machine-readable formats, which is known as Optical Chemical Structure Recognition (OCSR). Most OCSR systems developed over the last three decades use a rule-based approach, which vectorizes the depiction based on the interpretation of vectors and nodes as bonds and atoms. Here, we present a practical software called MolMiner, which is primarily built using deep neural networks originally developed for semantic segmentation and object detection to recognize atom and bond elements from documents. These recognized elements can be easily connected as a molecular graph with a distance-based construction algorithm. MolMiner gave state-of-the-art performance on four benchmark data sets and a self-collected external data set from scientific papers. As MolMiner performed similarly well in real-world OCSR tasks with a user-friendly interface, it is a useful and valuable tool for daily applications. The free download links of Mac and Windows versions are available at https://github.com/iipharma/pharmamind-molminer.

CavitySpace: A Database of Potential Ligand Binding Sites in the Human Proteome.

Location and properties of ligand binding sites provide important information to uncover protein functions and to direct structure-based drug design approaches. However, as binding site detection depends on the three-dimensional (3D) structural data of proteins, functional analysis based on protein ligand binding sites is formidable for proteins without structural information. Recent developments in protein structure prediction and the 3D structures built by AlphaFold provide an unprecedented opportunity for analyzing ligand binding sites in human proteins. Here, we constructed the CavitySpace database, the first pocket library for all the proteins in the human proteome, using a widely-applied ligand binding site detection program CAVITY. Our analysis showed that known ligand binding sites could be well recovered. We grouped the predicted binding sites according to their similarity which can be used in protein function prediction and drug repurposing studies. Novel binding sites in highly reliable predicted structure regions provide new opportunities for drug discovery. Our CavitySpace is freely available and provides a valuable tool for drug discovery and protein function studies.

Donor manipulation for constructing a pH sensing thermally activated delayed fluorescent probe to detect alkaliphiles.

pH homeostasis is essential for alkaliphiles, given their widespread use in biotechnological applications. However, quantitative monitoring of alkaline pH in alkaliphiles remains challenging. Here, we synthesized for the first time, a thermally activated delayed fluorescent (TADF) pH probe: NI-D-OH. Our probe exhibits a good linear relationship between fluorescence intensity and pH in the neutral to alkaline range (pH 7.0-8.6), as well as long-lived TADF emission. We further show that NI-D-OH can be used to monitor intracellular pH in living organisms, and evaluate the effect of Na+ on the pH homeostasis, demonstrating the potential for alkaline pH monitoring and time-resolved fluorescence imaging.

Prediction of liquid-liquid phase separating proteins using machine learning.

BACKGROUND: The liquid-liquid phase separation (LLPS) of biomolecules in cell underpins the formation of membraneless organelles, which are the condensates of protein, nucleic acid, or both, and play critical roles in cellular function. Dysregulation of LLPS is implicated in a number of diseases. Although the LLPS of biomolecules has been investigated intensively in recent years, the knowledge of the prevalence and distribution of phase separation proteins (PSPs) is still lag behind. Development of computational methods to predict PSPs is therefore of great importance for comprehensive understanding of the biological function of LLPS. RESULTS: Based on the PSPs collected in LLPSDB, we developed a sequence-based prediction tool for LLPS proteins (PSPredictor), which is an attempt at general purpose of PSP prediction that does not depend on specific protein types. Our method combines the componential and sequential information during the protein embedding stage, and, adopts the machine learning algorithm for final predicting. The proposed method achieves a tenfold cross-validation accuracy of 94.71%, and outperforms previously reported PSPs prediction tools. For further applications, we built a user-friendly PSPredictor web server ( http://www.pkumdl.cn/PSPredictor ), which is accessible for prediction of potential PSPs. CONCLUSIONS: PSPredictor could identifie novel scaffold proteins for stress granules and predict PSPs candidates in the human genome for further study. For further applications, we built a user-friendly PSPredictor web server ( http://www.pkumdl.cn/PSPredictor ), which provides valuable information for potential PSPs recognition.

Uncovering the Dominant Motion Modes of Allosteric Regulation Improves Allosteric Site Prediction.

Allostery is an important mechanism that biological systems use to regulate function at a distant site. Allosteric drugs have attracted much attention in recent years due to their high specificity and the possibility of overcoming existing drug-resistant mutations. However, the discovery of allosteric drugs remains challenging as allosteric regulation mechanisms are not clearly understood and allosteric sites cannot be accurately predicted. In this study, we analyzed the dominant modes that determine motion correlations between allosteric and orthosteric sites using the Gaussian network model and found that motion correlations between allosteric and orthosteric sites are dominated by either fast or slow vibrational modes. This dependence of modes results from the relative locations of the two sites and local secondary structures. Based on these analyses, we developed CorrSite2.0 to predict allosteric sites by taking the maximum of the Z-scores calculated from using either slow or fast modes. The prediction accuracy of CorrSite2.0 outperformed other commonly used allosteric site prediction methods with prediction accuracy over 90.0%. Our study uncovers the relationship of protein structure, dynamics, and allosteric regulation and demonstrates that using the dominant motion modes greatly improves allosteric site prediction accuracy. CorrSite2.0 has been integrated into the CavityPlus web server, which can be accessed at http://www.pkumdl.cn/cavityplus. CorrSite2.0 provides a powerful and user-friendly tool for allosteric drug and protein design.

miDruglikeness: Subdivisional Drug-Likeness Prediction Models Using Active Ensemble Learning Strategies.

The drug development pipeline involves several stages including in vitro assays, in vivo assays, and clinical trials. For candidate selection, it is important to consider that a compound will successfully pass through these stages. Using graph neural networks, we developed three subdivisional models to individually predict the capacity of a compound to enter in vivo testing, clinical trials, and market approval stages. Furthermore, we proposed a strategy combing both active learning and ensemble learning to improve the quality of the models. The models achieved satisfactory performance in the internal test datasets and four self-collected external test datasets. We also employed the models as a general index to make an evaluation on a widely known benchmark dataset DEKOIS 2.0, and surprisingly found a powerful ability on virtual screening tasks. Our model system (termed as miDruglikeness) provides a comprehensive drug-likeness prediction tool for drug discovery and development.

Design, synthesis, and biological evaluation of cyano-substituted 2,4-diarylaminopyrimidines as potent JAK3 inhibitors for the treatment of B-cell lymphoma.

A series of cyano-substituted 2,4-diarylaminopyrimidines was designed and synthesized as potent non-covalent JAK3 inhibitors. Among the derivatives synthesized, 9o (IC50 = 22.86 nM), 9 k (IC50 = 21.58 nM), and 9j (IC50 = 20.66 nM) demonstrated inhibitory potencies against JAK3 similar to the known JAK3 inhibitor tofacitinib (IC50 = 20.10 nM). Moreover, 9o displayed potent anti-proliferative activities against Raji and Ramos cells, with IC50 values of 0.9255 µM and 1.405 µM, respectively. In addition, 9o demonstrated low toxicity in normal HBE (human bronchial epithelial cells, IC50 > 10 µΜ) and L-02 (human liver cells, IC50 = 3.104 µΜ) cells. Analysis of the mode of action by flow cytometry indicated that 9o effectively arrested Raji cells at the G2/M phase. Taken together, these results suggested that 9o might be a promising candidate for development as a potential treatment for B-cell lymphoma.

Noncovalent EGFR T790M/L858R inhibitors based on diphenylpyrimidine scaffold: Design, synthesis, and bioactivity evaluation for the treatment of NSCLC.

A series of diphenylpyrimidine derivatives bearing a hydroxamic acid group was designed and synthesized as noncovalent EGFRT790M/L858R inhibitors to improve the biological activity and selectivity. One of the most promising compound 9d effectively interfered EGFRT790M/L858R binding with ATP and suppressed the proliferation of H1975 cells with IC50 values of 1.097 nM and 0.09777 µM, respectively. Moreover, compound 9d also not only exhibited a high selective index of 43.4 for EGFRT790M/L858R over the wild-type and 10.9 for H1975 cells over A431, but also exhibited low toxicity against the normal HBE cells (IC50 > 20 µΜ). In addition, the action mechanism validated that compound 9d effectively inhibited cell migration and promoted cell apoptosis by blocking cell cycle at G2/M stage. Furthermore, the target dose-dependently downregulated the expression of p-EGFR and arrested the activation of downstream Akt and ERK in H1975. All these studies provide important clues for the discovery of potent noncovalent EGFRT790M/L858R inhibitors.

Design, synthesis, and biological evaluation of hydroxamic acid-substituted 2,4-diaryl aminopyrimidines as potent EGFRT790M/L858R inhibitors for the treatment of NSCLC.

A series of 2,4-diarylaminopyrimidine derivatives bearing hydrophilic hydroxamic acids were designed and synthesized as potent EGFRT790M/L858R inhibitors. Among the derivatives synthesized, 10c (IC50 = 5.192 nM), 10j (IC50 = 10.35 nM), and 10o (IC50 = 0.3524 nM) exhibited higher potencies against EGFRT790/M/L858R compared to the known EGFR inhibitor AZD-9291 (IC50 = 20.80 nM). Moreover, 10j showed moderate activity against H1975 cells transfected with the EGFRT790M/L858R mutant, with an IC50 of 0.2113 µM over A431 (wild-type EGFR, SI = 47.3). In addition, 10j exhibited low toxicity in normal HBE cells (human bronchial epithelial cells, IC50 > 40 µΜ). Analysis of the mode of action indicated that 10j effectively induced apoptosis in H1975 cells by arresting the cells in the G2/M phase. Compound 10j also demonstrated efficacy in inhibiting tumor growth in a H1975 xenograft mouse model without losing body weight or killing the mice. Taken together, these results suggested that 10j might be a promising candidate for development as a potential treatment for NSCLC harboring the EGFRT790M/L858R mutation.