Small molecule inhibitors of RORγt for Th17 regulation in inflammatory and autoimmune diseases / 药物分析学报

As a ligand-dependent transcription factor,retinoid-associated orphan receptor γt(RORyt)that controls T helper(Th)17 cell differentiation and interleukin(IL)-17 expression plays a critical role in the pro-gression of several inflammatory and autoimmune conditions.An emerging novel approach to the therapy of these diseases thus involves controlling the transcriptional capacity of RORyt to decrease Th17 cell development and IL-17 production.Several RORyt inhibitors including both antagonists and inverse agonists have been discovered to regulate the transcriptional activity of RORyt by binding to orthosteric-or allosteric-binding sites in the ligand-binding domain.Some of small-molecule inhibitors have entered clinical evaluations.Therefore,in current review,the role of RORyt in Th17 regulation and Th17-related inflammatory and autoimmune diseases was highlighted.Notably,the recently developed RORyt inhibitors were summarized,with an emphasis on their optimization from lead compounds,ef-ficacy,toxicity,mechanisms of action,and clinical trials.The limitations of current development in this area were also discussed to facilitate future research.

Pharmacokinetic study of small molecule inhibitor SYHA1809 in Beagle dogs / 中国药房

OBJECTIVE To study the pharmacokinetics of small molecule inhibitor SYHA1809 in Beagle dogs. METHODS LC-MS/MS method was adopted. Beagle dogs were randomly divided into single intravenous administration group （3.75 mg/kg）， single low-dose intragastric administration group （3.75 mg/kg）， single medium-dose intragastric administration group （7.5 mg/kg）， single high-dose intragastric administration group （15 mg/kg） and multiple intragastric administration group （7.5 mg/kg， once a day， for 7 consecutive days）， with 6 dogs in each group， half male and half female. The plasma samples of Beagle dogs were collected in each group according to the set time point， and underwent LC-MS/MS quantitative analysis after preprocessing. The pharmacokinetic parameters were calculated by using Phoenix WinNonlin 8.0 software using obtained data. RESULTS After intravenous injection， CL of SYHA1809 in Beagle dogs was （2.70±0.48） mL/（min·kg）， steady-state distribution volume was 0.757 L/kg， and t1/2 was （3.35±1.36） h； after single intragastric administration of low-dose， medium-dose and high-dose of SYHA1809， average tmax was （0.53±0.02） h， and the blood drug concentration increased with the increase of dose； after single intragastric administration of 3.75 mg/kg SYHA1809， the absolute bioavailability was 83.5%； within the dose range of 3.75-15 mg/kg， the increase in cmax and AUC of SYHA1809 was positively correlated with the dose； after intragastric administration of 7.5 mg/kg SYHA1809 for 7 consecutive days， the pharmacokinetic parameters of SYHA1809 were comparable to those of a single intragastric administration of the same dose， with no statistically significant difference （P＞0.05）. CONCLUSIONS SYHA1809 is absorbed rapidly in Beagle dogs， shows the dose-dependent blood concentration， high bioavailability， no obvious accumulation after multiple intragastric administration， and good pharmacokinetic behavior.

Recent advances in small molecule inhibitors of interleukin‑1 receptor-associated kinase / 药学学报

Interleukin-1 receptor associated kinase 4 (IRAK-4), acting as a serine threonine kinase, is considered as a key signal node for the transduction of IL-1R family and TLRs signal pathway. Studies have found that IRAK-4 has a hand in many signal pathways, involving the inflammatory response of human joints, intestines, liver and nervous system, as well as other autoimmune diseases. It is also one of the causes of drug resistance of some cancer cells. Therefore, IRAK-4 tends to be an effective therapeutic target for inflammatory diseases and cancer. The prospects for the development of drugs in this pathway is to develop novel IRAK-4 small molecule inhibitors and investigate their safety and effectiveness, enrich the clinical treatment of inflammatory and cancer diseases finally. This paper classified and summarized the latest research progress on small molecule inhibitors of IRAK-4 signaling pathway according to structures of the compounds, in order to provide assistances and references for the research and development of related drugs.

Recent advances in small-molecule inhibitors targeting influenza virus glycoproteins / 药学学报

Hemagglutinin and neuraminidase, two important glycoproteins on the surface of influenza virus, play a considerable role in the entry and release stage of the viral life cycle, respectively. With in-depth investigation of influenza virus glycoproteins and the continuous innovation of drug discovery strategies, a new generation of glycoproteins inhibitors have been continuously discovered. From the point of view of medicinal chemistry, this review summarizes the current advances in seeking small-molecule inhibitors targeting influenza virus glycoproteins, hoping to provide valuable guidance for future development of novel antiviral drugs.

Discovery of a small-molecule inhibitor of carbamoyl phosphate synthase 1 and its anti-colorectal cancer mechanism / 药学学报

The carbamoyl phosphate synthase 1 (CPS1) enzyme is involved in the first phase of the urea cycle, providing a prerequisite molecule for pyrimidine synthesis, as well as promoting tumor cell proliferation and growth. Studies have found that CPS1 is highly expressed in a variety of tumors, including colorectal cancer, lung cancer, etc. and its overexpression is related to the poor prognosis of tumors. Thus, small molecules targeted to inhibit the function of CPS1 in tumors may provide therapeutic benefits for cancer patients who overexpress CPS1. In this study, the function of CPS1 was investigated in vitro, and we found that overexpression of CPS1 can enhance the migration ability of colorectal cancer cells HCT15. Here, based upon the existing crystal structure, combined with high-throughput virtual screening, we obtained 8 candidate small molecule compounds. In vitro activity evaluation, we found that compound 3 has good anti-HCT15, HCT116 cell proliferation activity (HCT15, IC50, 7.69 ± 1.10 μmol‧L-1, HCT116, IC50, 13.53 ± 0.46 μmol‧L-1). Subsequently, molecular docking and molecular dynamics (MD) simulation analysis showed that, compound 3 could target and inhibit the activity of CPS1. In vitro studies showed that compound 3 could inhibit the migration of HCT15 cells, as well as induced cell cycle arrest and apoptosis. Taken together, this study found that compound 3 is a potential small molecule inhibitor that targets CPS1, which provides the experimental basis and theoretical basis for the development of targeted intervention small molecule therapeutic drugs. Based upon the chemical structure of compound 3, we will shed new light on further optimizing its activity and therapeutic potential, which may provide a therapeutic benefit to the patients with CPS1-related tumors.

Effect of Curcumin on Apoptosis of Acute T-Lymphoblastic Leukemia Cells induced by UMI-77 and Its Related Mechanism / 中国实验血液学杂志

AbstractObjective: To explore the effect and mechanism of curcumin on human T-cell acute lymphoblastic leukemia (T-ALL) cell apoptosis induced by Mcl-1 small molecule inhibitors UMI-77.@*METHODS@#T-ALL cell line Molt-4 was cultured, and the cells were treated with different concentrations of curcumin and Mcl-1 small molecule inhibitor UMI-77 for 24 h. The MTT method was used to detect the cell survival rate after different treatment; According to the results of curcumin and UMI-77, the experimental settings were divided into control group, curcumin group (20 μmol/L curcumin treated cells), UMI-77 group (15 μmol/L Mcl-1 small molecule inhibitor UMI-77 treated cells) and curcumin+ UMI-77 group (20 μmol/L curcumin and 15 μmol/L Mcl-1 small molecule inhibitor UMI-77 treated cells), MTT method was used to detect cell proliferation inhibition rate, Annexin V-FITC/PI double staining method and TUNEL staining were used to detect cell apoptosis, DCFH-DA probe was used to detect cell reactive oxygen species, JC-1 fluorescent probe was used to detect mitochondrial membrane potential, Western blot was used to detect the expression levels of apoptosis-related proteins and Notch1 signaling pathway-related proteins.@*RESULTS@#After the treatment of Molt-4 cells with different concentrations of curcumin and Mcl-1 small molecule inhibitor UMI-77, the cell survival rate was decreased (P<0.05); Compared with the control group, the cell proliferation inhibition rate of the curcumin group and the UMI-77 group were increased, the apoptosis rate of cell was increased, the level of ROS was increased, the protein expression of Bax, Caspase-3 and Caspase-9 in the cells were all increased, and the protein expression of Bcl-2 was reduced (P<0.05); Compared with the curcumin group or UMI-77 group, the cell proliferation inhibition rate and apoptosis rate of the curcumin+UMI-77 group were further increased, and the level of ROS was increased. At the same time, the protein expression of Bax, Caspase-3 and Caspase-9 in the cells were all increased, the protein expression of Bcl-2 was reduced (P<0.05); In addition, the mitochondrial membrane potential of the cells after curcumin treatment was decreased, and the proteins expression of Notch1 and HES1 were reduced (P<0.05).@*CONCLUSION@#Curcumin can enhance the apoptosis of T-ALL cells induced by Mcl-1 small molecule inhibitor UMI-77 by reducing the mitochondrial membrane potential, the mechanism may be related to the inhibition of Notch1 signaling pathway.

Advances of inhibitors targeting MLL1-WDR5 protein-protein interaction / 中国药科大学学报

@#Mixed lineage leukemia 1(MLL1) is a member of the "SET" histone methyltransferases family.MLL1 methyltransferase complex, consisting of MLL1, WDR5, RbBP5, Ash2L and DPY-30, regulates methylation level of histone H3 lysine 4 and is essential for the development of human hematopoietic system and self-renewal of blood cells.As an oncogenic protein produced by the translocation of MLL1 gene, the MLL1 fusion protein has been found in some patients with leukemia.Complete MLL1 enzyme complex is required to perform histone demethylation effect, therefore, targeting the protein-protein interaction of MLL1-WDR5 has become a potential strategy for the treatment of leukemia induced by MLL1 fusion protein.This review systematically summarizes the biological mechanism, structural information and inhibitors of MLL1-WDR5 protein-protein interaction, with a perspective based on previously reported data, aiming to provide some reference for further investigation.

FGFR4: a promising therapeutic target for liver cancer / 药学学报

Fibroblast growth factor receptor (FGFR), as a member of the receptor tyrosine kinase family, participates in a variety of biological processes by binding to ligand fibroblast growth factors (FGFs) and activating downstream signaling pathways, such as cell proliferation, migration, anti-apoptosis, angiogenesis, etc. FGFR gene amplification, missense mutations, oncogenic fusion are related to the occurrence and development of many cancers. FGFR has become an important potential target in cancer treatment. At present most of these studies focus on FGFR1-3, however there is growing evidence implicating an important and unique role of FGFR4 in oncogenesis and resistance to anti-tumor therapy in multiple types of cancer. The abnormality of FGF19-FGFR4 signaling pathway has been proved to be a carcinogenic factor of liver cancer. Importantly, there are several novel FGFR4-specific inhibitors in clinical trials, FGFR4 is therefore a promising target for the treatment of hepatocellular carcinoma harboring aberrant FGF19-FGFR4 signaling. In this review, we focus on assessing the role of FGFR4 in liver cancer, including a summary of the structure and ligand of FGFR4, downstream signaling pathways, abnormal activation in liver cancer, and the research progress of small molecule FGFR4 inhibitors, FGFR4 monoclonal antibodies and combined immunotherapy.

Advances in drug research targeting the Wnt signaling pathway in colorectal cancer / 药学学报

Colorectal cancer is a common malignant tumor in the gastrointestinal tract, with the characteristics of high morbidity and mortality. Studies have shown that the occurrence and development of colorectal cancer is closely related to the abnormal activation of Wnt signaling pathway. Abnormal expression of β-catenin in Wnt pathway is found both in the cytoplasm and nucleus of tumor cells. Different drugs can target the Wnt signaling pathway and its upstream and downstream related factors to inhibit or suppress the development of colorectal cancer. We review the components of Wnt signaling pathway, and the correlation between Wnt signaling pathway and colorectal cancer. Then, we summarize the current status of drug research targeting the Wnt signaling pathway in colorectal cancer. Finally, the challenges and prospects of these methods and drugs were briefly summarized.

Discovery of a small molecule inhibitor of cullin neddylation that triggers ER stress to induce autophagy

Protein neddylation is catalyzed by a three-enzyme cascade, namely an E1 NEDD8-activating enzyme (NAE), one of two E2 NEDD8 conjugation enzymes and one of several E3 NEDD8 ligases. The physiological substrates of neddylation are the family members of cullin, the scaffold component of cullin RING ligases (CRLs). Currently, a potent E1 inhibitor, MLN4924, also known as pevonedistat, is in several clinical trials for anti-cancer therapy. Here we report the discovery, through virtual screening and structural modifications, of a small molecule compound HA-1141 that directly binds to NAE in both

Recent progress in targeting degradation of FAK based on PROTAC / 药学学报

Local focal adhesion kinase (FAK) is a non-receptor intracellular tyrosine kinase that plays an important role in tumor initiation, development, metastasis and invasion, and is considered to be an important target for the development of antineoplastic drugs. It has both kinase-dependent and non-kinase-dependent scaffolding functions. However, traditional small molecular inhibitors can only inhibit its kinase-dependent activity, so it is difficult to target the kinase-independent scaffolding function. Therefore, there is an urgent need for novel strategies to enhance FAK targeting to lay the foundation for determining the druggability and discovery of FAK inhibitors. Proteolysis targeting chimera (PROTAC) is a new drug development strategy that can recruit E3 ligase to specifically ubiquitinylate target proteins for degradation through the proteasome system. The unique mechanism of action of the PROTAC system could be used to target and degrade the FAK protein, thus eliminating the scaffolding function of FAK. In this review, FAK protein, the signaling pathway, and small molecule inhibitors are briefly described, and the latest research progress in targeting the degradation of FAK using PROTAC technology is summarized.

Research progress of KRAS inhibitors / 药学学报

The RAS (rat sarcoma) gene is one of the important oncogenes, and its mutation is present in about 30% human tumors. KRAS (kirsten rat sarcoma viral oncogene) is one of the three RAS subtypes, and KRAS mutations are more common than the mutations in other two RAS subtypes. In recent years, with the continuous research, new ideas have been provided for the treatment of cancers via targeting-KRAS. Efforts have been made to develop various KRAS inhibitors. Here, based on the mechanism of action, we classified KRAS inhibitors into two categories: inhibitors that directly target KRAS and inhibitors that indirectly act on KRAS. The representative KRAS inhibitors were summarized and introduced in this paper.

Virtual screening of small molecular inhibitors of SARS-CoV-2 3CL hydrolase based on high-throughput molecular docking and prediction of Chinese materia medica and its compound against COVID-19 / 中草药

Objective: Based on the systematic pharmacological database of traditional Chinese medicine (TCM) and the analysis platform TCMSP, the computer virtual screening technique was used to screen the small molecule inhibitors of SARS-CoV-2 3CL hydrolase from Chinese materia medica (CMM), and speculate the potential anti-COVID-19 novel coronavirus pneumonia TCMs and its compounds. Methods: SARS-CoV-2 3CL hydrolase protein was targeted in this study. Autodock Vina software and Python script were used to realize high-throughput molecular docking. Combined with “ADME-Lipinski” rules, the re-screening was carried out to optimize the active ingredients and speculate the key TCMs and compound prescriptions. Based on the perspective of network pharmacology, a component-target-pathway network was constructed to infer the mechanism of action of core drug pairs. Results: Taking the reference ligand as positive control, 66 natural micromolecule compounds with good pharmacokinetic properties were obtained. Twelve single TCMs, two Chinese medicine pairs of Glycyrrhizae Radix et Rhizoma-Mori Cortex and Lonicerae Japonicae Flos-Forsythiae Fructus, and 12 TCM prescriptions including Sangju Drink and modified Sangju Drink and Yinqiao Powder were selected as candidate schemes to fight against novel coronavirus pneumonia. Conclusion: This study is based on high-throughput molecular docking technology to virtually screen small molecule inhibitors of SARS-CoV-2 3CL hydrolase of CMM and Chinese medicines, innovatively analyze the potential molecular mechanism in combination with network pharmacology, and provide scientific guidance and theoretical basis for TCM to resist novel coronavirus pneumonia.

Advances in small molecule inhibitors of ACK1 / 药学学报

ACK1 (activated Cdc42-associated kinase) is a non-receptor tyrosine kinase, originally identified by its binding to the GTP-binding small GTPase Cdc42. It is widely expressed in human tissues and activated by various extracellular growth factors such as EGF, PDGF and TGF-β. The activated ACK1 mediates the signaling cascade by interacting with downstream effectors followed by their phosphorylation. In recent years, researchers have investigated the biological functions of ACK1 and its roles in cancer research. The gene amplification and overexpression of ACK1 is associated with a poor prognosis and metastasis in a variety of cancers including lung, ovarian and prostate cancers. Therefore, the development of small molecule inhibitors of ACK1 provides promising opportunities for cancer-targeted therapy. In this review, we briefly describe recent advances in understanding the activation and biological function of ACK1 and introduce its novel inhibitors with potential therapeutic activities in preclinical studies.

Recent advances in the discovery and development of adenovirus inhibitors / 药学学报

Adenovirus is a common cause of infection in children and adults with acute respiratory tract, gastrointestinal tract and urinary tract. It can cause serious and even fatal infections in patients with low immune function. Therefore, it poses a great threat to human health. Currently, there are no specific anti-adenoviral drugs in market. With in-depth investigation of the pathogenic mechanism and biological characteristics of adenovirus, and the rapid development of drug screening technology, new generation of anti-adenovirus drug targets and related inhibitors have been discovered, providing new options for treatment. This review selects the representative case studies in recent years and summarizes the advances in anti-adenoviral medicinal chemistry.

Recent progress in inhibitors against hepatitis C virus / 药学学报

Hepatitis C virus (HCV) infection is one of the global public health issues. Approximately, 130-150 million individuals are chronically infected worldwide and a quarter of these patients are at increased risk of developing liver cirrhosis, hepatocellular carcinoma and even liver failure. A complete eradication of the virus is one of the most important treatment goals for antiviral research. From the point of view of medicinal chemistry, we summarize and discuss current endeavors towards the discovery and development of novel inhibitors with various scaffolds or distinct mechanisms of action.

Progress on IFV drug targets and small molecule inhibitors / 药学学报

The outbreak of the influenza viruses (IFV) caused significant harm to our health and life. Human infections caused by pathogenic avian influenza virus (AIV) have continually brought great panic and death threats to people all over the world. With the in-depth study of the biological characteristics of influenza viruses and the rapid development of drug discovery screening technology, a new generation of anti-influenza drug targets and their inhibitors have been continuously discovered, providing more options for the treatment of influenza. From the point of view of medicinal chemistry, this review summarizes and discusses current endeavours towards the discovery and development of novel inhibitors and also provides examples illustrating new methodologies that contribute to the identification of novel anti-influenza drugs.

Research on anti-non-small cell lung cancer activity of ornithine decarboxylase anti-enzyme inhibitor-1 small molecule inhibitor / 中国药理学通报

Aim To investigate the inhibitory effect of small molecule inhibitors of ornithine decarboxylase inhibitor 1 (AZIN-1) on non-small cell lung cancer and its mechanism. Methods Cell proliferation was detected by Cell Counting Kit-8 (CCK-8). Apoptosis was analyzed by flow cytometry (PI/Annexin V-FITC double staining). The expression of ornithine decarboxylase (ODC), ornithine decarboxylase anti-enzyme-1 (AZ-1) and AZIN-1 was detected by Western blot. Cell cycle was analyzed by flow cytometry (PI single staining). The total polyamine content in cellswas measured by high performance liquid chromatography (HPLC). Results Small molecule inhibitor of AZIN-1 could significantly inhibit the proliferation of A549 cells, cause G0/G, cycle arrest, induce apoptosis of A549 cells, inhibit the expression of AZIN-1 and ODC, interfere with intracellular polyamine metabolism, and reduce total polyamine content in cells. Conclusions Small molecule inhibitor of AZIN-1 has significant growth inhibitory effect on A549 cells, and its mechanism may be related to the induction of apoptosis and interference with polyamine metabolism.

Advances in small molecule inhibitors of PD-1/PD-L1 immune checkpoint pathway / 中国药科大学学报

@#Studies have found that a variety of tumors continue to activate PD-1(programmed cell death protein 1, PD-1)/PD-L1(programmed cell death-ligand 1)signaling pathway by up-regulating PD-L1 expression in tumor cells and microenvironment. The dysfunction of T cells leads to the occurrence of tumor immune escape. Several PD-1/PD-L1 monoclonal antibodies have been marketed to achieve significant clinical efficacy. However, because of the high production cost, the harsh conditions for storage and transportation, and the potential immunogenicity of monoclonal antibody, the seeking for PD-1/PD-L1 small molecule inhibitors has become a hot spot in the development of new drugs. In this paper, the biological mechanisms of PD-1/PD-L1 was introduced in detail. Based on the structural classification, the research progress of PD-1/PD-L1 small molecule inhibitors was reviewed, with a prospect of the development of small molecule inhibitors.

Research progresses of small molecule inhibitors targeting TGF-β and its receptors / 药学学报

Transforming growth factor-β (TGF-β) belongs to a group of biologically active cytokines that bind to its receptors to activate Smad signaling and non-Smad signaling pathways. The biological functions of TGF-β include promoting cell epithelial-mesenchymal transition, tissue fibrosis, angiogenesis and tumor immune evasion, as well as dual effects of cancer suppression and cancer promotion. Given the fact that the ligand- and receptors-mediated abnormal activation of TGF-β signaling pathways play an important role in the pathogenesis of multiple diseases such as malignant tumors and tissue fibrosis, more than a dozen small-molecule inhibitors have been developed to block the TGF-β signaling pathways, providing a novel method for controlling the development of these diseases. At present, pirfenidone, an inhibitor for TGF-β production, has been approved for treatment of idiopathic pulmonary fibrosis, while the inhibitors of TGFβRI/ALK5 for therapeutics of tumors or myelodysplastic syndromes, including LY2157299, EW-7197 and LY3200882, are in the phase I to III clinical trials, with additional ones inhibiting TGFβRs such as SB-431542, LY2109761, TP-0427736, and IN-1130 being in the preclinical phase. This paper reviews recent advances in research of small-molecule inhibitors targeting TGF-β and its receptors.