Races of small molecule clinical trials for the treatment of COVID-19: An up-to-date comprehensive review.

The coronavirus disease-19 (COVID-19) pandemic has become a global threat since its first outbreak at the end of 2019. Several review articles have been published recently, focusing on the aspects of target biology, drug repurposing, and mechanisms of action (MOAs) for potential treatment. This review gathers all small molecules currently in active clinical trials, categorizes them into six sub-classes, and summarizes their clinical progress. The aim is to provide the researchers from both pharmaceutical industries and academic institutes with the handful information and dataset to accelerate their research programs in searching effective small molecule therapy for treatment of COVID-19.

Design, synthesis, and biological evaluation of novel 2-methylpiperazine derivatives as potent CCR5 antagonists.

Three series of novel 2-methylpiperazine derivatives were designed and synthesized using a fragment-assembly strategy. Among them, six compounds (13, 16, 18, 22, 33, and 36) showed potent activity against CCR5 comparable to that of the positive control, maraviroc, in calcium mobilization assay. Moreover, some compounds were selected and further tested for their antiviral activity in HIV-1 single cycle assay. As a result, four compounds (13, 16, 33, and 36) showed antiviral activity at the nanomolar level. Additionally, the potent four compounds showed no cytotoxicity at a concentration of 10µM.

Growth and metastasis suppression of glioma xenografts expressing exon 4-deletion variant of epidermal growth factor receptor by monoclonal antibody CH12-mediated receptor degradation.

We recently isolated an exon-4-deleted epidermal growth factor receptor (EGFR) variant, termed de4 EGFR. Because the extracellular domain alteration of receptors often influences the antitumor effect of therapeutic antibodies, it is essential to test the sensitivity of de4 EGFR(+) tumors to anti-EGFR antibodies. Therefore, in this study, the antitumor activities of mAb CH12, an anti-EGFRvIII antibody developed in our laboratory, as well as a U.S. Food and Drug Administration-approved anti-EGFR antibody, cetuximab (C225), were characterized on de4 EGFR(+) models. The results of FACS assays showed that CH12 bound to de4 EGFR with a higher avidity than did C225. Interestingly, CH12, but not C225, significantly inhibited the metastasis and growth of U87MG-de4 EGFR xenografts, with a growth-inhibition ratio of 46.48% in vivo, and prolonged the survival of the tumor-bearing mice by 37.2%. Treatment with CH12 significantly suppressed tumor proliferation and angiogenesis with increased tumor apoptosis. Mechanistically, de4 EGFR protein expression was virtually undetectable in the U87MG-de4 EGFR xenografts treated with CH12. This may account for the observed reduction of Akt and Erk phosphorylation, cyclin D1, Bcl-2, and Bcl-x(L) expression and the increase of p27 and E-cadherin expression. Intriguingly, LAMP-1, a major component of the lysosome, was significantly up-regulated in the CH12-treated group but not in the C225-treated group, suggesting its contribution to the degradation of de4 EGFR. Taken together, our data demonstrated that mAb CH12 is a promising therapeutic agent for treating de4 EGFR(+) gliomas.

Growth suppression of human hepatocellular carcinoma xenografts by a monoclonal antibody CH12 directed to epidermal growth factor receptor variant III.

Human hepatocellular carcinoma (HCC) is considered difficult to cure because it is resistant to radio- and chemotherapy and has a high recurrence rate after curative liver resection. Epidermal growth factor receptor variant III (EGFRvIII) has been reported to express in HCC tissues and cell lines. This article describes the efficacy of an anti-EGFRvIII monoclonal antibody (mAb CH12) in the treatment of HCC xenografts with EGFRvIII expression and the underlying mechanism of EGFRvIII as an oncogene in HCC. The results demonstrated that CH12 bound preferentially to EGFRvIII with a dissociation constant (K(d)) of 1.346 nm/liter. In addition, CH12 induces strong antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity in Huh7-EGFRvIII (with exogenous expression of EGFRvIII) and SMMC-7721 (with endogenous expression of EGFRvIII) cells. Notably, CH12 significantly inhibited the growth of Huh7-EGFRvIII and SMMC-7721 xenografts in vivo with a growth inhibition ratio much higher than C225, a U. S. Food and Drug Administration-approved anti-EGFR antibody. Treatment of the two HCC xenografts with CH12 significantly suppressed tumor proliferation and angiogenesis. Mechanistically, in vivo treatment with CH12 reduced the phosphorylation of constitutively active EGFRvIII, Akt, and ERK. Down-regulation of the apoptotic protectors Bcl-x(L), Bcl-2, and the cell cycle regulator cyclin D1, as well as up-regulation of the cell-cycle inhibitor p27, were also observed after in vivo CH12 treatment. Collectively, these results indicate that the monoclonal antibody CH12 is a promising therapeutic agent for HCC with EGFRvIII expression.

Design, synthesis and inhibitory activities of 8-(substituted styrol-formamido)phenyl-xanthine derivatives on monoamine oxidase B.

The design and synthesis of two series of 8-(substituted styrol-formamido)phenyl-xanthine derivatives are described. Their in vitro monoamine oxidase B (MAO-B) inhibition were tested and the effect of substituents on the N-7, phenyl and the substituted positions are discussed. It was observed that compound 9b displayed significant MAO-B inhibition activity and selectivity, fluorine substitution plays a key role in the selectivity of MAO-B inhibition, and the styrol-formamido group at position-3' may enhance the activity and selectivity of 8-phenyl-xanthine analogues. These results suggest that such compounds may be utilized for the development of new candidate MAO-B inhibitors for treatment of Parkinson's disease.

Characteristics and independent predictors of self-disclosure among male patients undergoing in vitro fertilization: A cross-sectional study.

PURPOSE: To investigate the levels of self-disclosure in men undergoing in vitro fertilization and analyze the effects of communication and personality on self-disclosure. DESIGN AND METHODS: This cross-sectional study included 210 men undergoing in vitro fertilization. Self-disclosure was measured using the Chinese Distress Disclosure Index Scale. FINDINGS: Participants with high self-disclosure exhibited lower neuroticism, higher extraversion, better partner communication, higher educational levels, and were likely to have a child; these factors were independent predictors of self-disclosure. PRACTICE IMPLICATIONS: These findings highlight the factors influencing self-disclosure and can aid in developing guidance programs for infertile men.

Discovery of small-molecule ATR inhibitors for potential cancer treatment: a patent review from 2014 to present.

INTRODUCTION: Ataxia telangiectasia and RAD3-related kinase (ATR) is one of the key phosphatidylinositol 3-kinase-related kinase family members important for DNA damage response and repair pathways. Targeting ATR kinase for potential cancer therapy has attracted a great deal of attention to both pharmaceutical industries and academic community. AREA COVERED: This article surveys the patents published since 2014 aiming to analyze the structural features of scaffolds and the patent space. It also discusses the recent clinical developments and provides perspectives on the challenges and the future directions. EXPERT OPINION: ATR kinase appears to be a viable drug target for anticancer therapy. Similar to DNA-PK inhibitors, the clinical investigation of an ATRi employs both monotherapy and combination strategy. In the combination strategy, an ATRi is typically combined with a radiation or a targeted drug such as chemotherapy agent poly (ADP-ribose) polymerase (PARP) inhibitor, etc. Diverse structures comprising different scaffolds from mono-heteroaryl to bicyclic heteroaryl to tricyclic heteroaryl to macrocycle are capable of achieving good ATR inhibitory activity and good ATR selectivity over other closely related enzymes. There are eight ATR inhibitors currently being evaluated in clinics, with the hope to get approval in the near future.

A Bibliometric Analysis of the Association Between Compassion Fatigue and Psychological Resilience From 2008 to 2021.

Aims: A negative association between the lower level of psychological resilience (PR) and increased risk of compassion fatigue (CF) and higher Coronavirus disease 2019 (COVID-19) stress has been revealed. However, bibliometric studies have not been performed to comprehensively investigate this topic. This study aimed to identify the status and trends in the CF and PR field from 2008 to 2021 and during the COVID-19 pandemic. Methods: We identified relevant literature from the Web of Science Core Collection® database using "resilience" and "compassion fatigue" on September 30, 2021. All search results were exported in plain text format for collaboration network analysis, reference-based co-citation analysis, analysis of journals, and keywords-based co-occurrence analysis, which were performed using Citespace® 5.8.R1. Results: A total of 388 publications were identified finally, and there has been an increasing trend in the annual number of publications with light fluctuations. The analysis of journals and keywords indicated that nurses and social workers are the main research targets, and their mental problems are the main research topics. The turnover intention of health care providers has been a research focus, particularly during the COVID-19. Conclusion: The results of the present study help us understand the status of the CF and PR field and its recent developments.

Small molecule DNA-PK inhibitors as potential cancer therapy: a patent review (2010-present).

Introduction: DNA-dependent protein kinase (DNA-PK) plays a crucial role in the repair of DSBs via non-homologous end joining (NHEJ). Several DNA-PK inhibitors are being investigated for potential anticancer treatment in clinical trials.Area covered: This review aims to give an overview of patents published since 2010 by analyzing the patent space and structure features of scaffolds used in those patents. It also discusses the recent clinical developments and provides perspectives on future challenges and directions in this field.Expert opinion: As a key component of the DNA damage response (DDR) pathway, DNA-PK appears to be a viable drug target for anticancer therapy. The clinical investigation of a DNA-PK inhibitor employs both a monotherapy and a combination strategy. In the combination strategy, a DNA-PK inhibitor is typically combined with a DSB inducer, radiation, a chemotherapy agent, or a PARP inhibitor, etc. Patent analyses suggest that diverse structures comprising different scaffolds from mono-heteroaryl to bicyclic heteroaryl to tricyclic heteroaryl are capable to achieve good DNA-PK inhibitory activity and good DNA-PK selectivity over other closely related enzymes. Several DNA-PK inhibitors are currently being evaluated in clinics, with the hope to get approval in the near future.

Design, synthesis, and biological evaluation of novel piperidine-4-carboxamide derivatives as potent CCR5 inhibitors.

Based on a putative 'Y shape' pharmacophore model of CCR5 inhibitors, a series of novel piperidine-4-carboxamide derivatives were designed and synthesized using a group-reverse strategy. Among synthesized target compounds, 16g (IC50 = 25.73 nM) and 16i (IC50 = 25.53 nM) showed equivalent inhibitory activity against CCR5 to that of the positive control maraviroc (IC50 = 25.43 nM) in calcium mobilization assay. Selected compounds were further tested for their antiviral activity in HIV-1 single cycle assay. Two compounds, 16g and 16i, displayed antiviral activity with IC50 values of 73.01 nM and 94.10 nM, respectively. Additionally, the pharmacokinetic properties and inhibitory potency against hERG of 16g were evaluated, providing a foundation for ongoing optimization.

The monoclonal antibody CH12 enhances the sorafenib-mediated growth inhibition of hepatocellular carcinoma xenografts expressing epidermal growth factor receptor variant III.

The multikinase inhibitor sorafenib is the first oral agent to show activity against human hepatocellular carcinoma (HCC). Although the clinical application of sorafenib has shown good tolerability in the studied populations, it also causes multiple human dose-limiting toxicities. Thus, there is a strong need to reduce the overall dose of sorafenib. We have reported that the epidermal growth factor receptor variant III (EGFRvIII) expression can decrease the sensitivity of HCC cells to chemotherapeutic drugs. Therefore, we sought to explore whether EGFRvIII can affect the sensitivity of HCC cells to sorafenib. In this study, we observed that EGFRvIII expression significantly decreased the sensitivity of HCC cells to sorafenib. To enhance the antitumor effect and reduce the overall dose of sorafenib, we evaluated the combined effects of CH12, a monoclonal antibody against EGFRvIII, and sorafenib on the growth of HCC cells expressing EGFRvIII in vitro and in vivo. The results showed that, when CH12 was combined with sorafenib, the tumor growth suppression effect was significantly increased, and the concentration of sorafenib required for growth inhibition was substantially reduced. Mechanistically, the combination could more noticeably downregulate the phosphorylation of constitutively active extracellular signal-regulated kinase (ERK), Akt (Thr308), and signal transducer and activator of transcription 3 (STAT3) than sorafenib alone. Collectively, these findings demonstrate that CH12 interacts additively with sorafenib to strongly inhibit the tumor growth of HCC xenografts expressing EGFRvIII by enhancing the sorafenib-mediated inhibition of the MEK/ERK, phosphoinositide 3-kinase/AKT, and STAT3 pathways.

Bioprocess development for the production of mouse-human chimeric anti-epidermal growth factor receptor vIII antibody C12 by suspension culture of recombinant Chinese hamster ovary cells.

The mouse-human chimeric anti-epidermal growth factor receptor vIII (EGFRvIII) antibody C12 is a promising candidate for the diagnosis of hepatocellular carcinoma (HCC). In this study, 3 processes were successfully developed to produce C12 by cultivation of recombinant Chinese hamster ovary (CHO-DG44) cells in serum-free medium. The effect of inoculum density was evaluated in batch cultures of shaker flasks to obtain the optimal inoculum density of 5 × 10(5) cells/mL. Then, the basic metabolic characteristics of CHO-C12 cells were studied in stirred bioreactor batch cultures. The results showed that the limiting concentrations of glucose and glutamine were 6 and 1 mM, respectively. The culture process consumed significant amounts of aspartate, glutamate, asparagine, serine, isoleucine, leucine, and lysine. Aspartate, glutamate, asparagine, and serine were particularly exhausted in the early growth stage, thus limiting cell growth and antibody synthesis. Based on these findings, fed-batch and perfusion processes in the bioreactor were successfully developed with a balanced amino acid feed strategy. Fed-batch and especially perfusion culture effectively maintained high cell viability to prolong the culture process. Furthermore, perfusion cultures maximized the efficiency of nutrient utilization; the mean yield coefficient of antibody to consumed glucose was 44.72 mg/g and the mean yield coefficient of glutamine to antibody was 721.40 mg/g. Finally, in small-scale bioreactor culture, the highest total amount of C12 antibody (1,854 mg) was realized in perfusion cultures. Therefore, perfusion culture appears to be the optimal process for small-scale production of C12 antibody by rCHO-C12 cells.