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CXCR4 antagonists have been claimed to reduce mortality after myocardial infarction in myocardial infarction (MI) animals, presumably due to suppressing inflammatory responses caused by myocardial ischemia-reperfusion injury, thus, subsequently facilitating tissue repair and cardiac function recovery. This study aims to determine whether a newly designed CXCR4 antagonist DBPR807 could exert better vascular-protective effects than other clinical counterparts (e.g., AMD3100) to alleviate cardiac damage further exacerbated by reperfusion. Consequently, we find that instead of traditional continuous treatment or multiple-dose treatment at different intervals of time, a single-dose treatment of DBPR807 before reperfusion in MI animals could attenuate inflammation via protecting oxidative stress damage and preserve vascular/capillary density and integrity via mobilizing endothelial progenitor cells, leading to a desirable fibrosis reduction and recovery of cardiac function, as evaluated with the LVEF (left ventricular ejection fraction) in infarcted hearts in rats and mini-pigs, respectively. Thus, it is highly suggested that CXCR4 antagonists should be given at a single high dose prior to reperfusion to provide the maximal cardiac functional improvement. Based on its favorable efficacy and safety profiles indicated in tested animals, DBPR807 has a great potential to serve as an adjunctive medicine for percutaneous coronary intervention (PCI) therapies in acute MI patients.

Tylophorine-based compounds and natural cardiotonic steroids (cardenolides and bufadienolides) are two classes of transmissible gastroenteritis coronavirus inhibitors, targeting viral RNA and host cell factors, respectively We tested both types of compounds against two types of coronaviruses, to compare and contrast their antiviral properties, and with view to their further therapeutic development Examples of both types of compounds potently inhibited the replication of both feline infectious peritonitis virus and human coronavirus OC43 with EC50 values of up to 8 and 16 nM, respectively Strikingly, the tylophorine-based compounds tested inhibited viral yields of HCoV-OC43 to a much greater extent (7–8 log magnitudes of p f u /ml) than the cardiotonic steroids (about 2–3 log magnitudes of p f u /ml), as determined by end point assays Based on these results, three tylophorine-based compounds were further examined for their anti-viral activities on two other human coronaviruses, HCoV-229E and SARS-CoV-2 These three tylophorine-based compounds inhibited HCoV-229E with EC50 values of up to 6 5 nM, inhibited viral yields of HCoV-229E by 6–7 log magnitudes of p f u /ml, and were also found to inhibit SARS-CoV-2 with EC50 values of up to 2 5–14 nM In conclusion, tylophorine-based compounds are potent, broad-spectrum inhibitors of coronaviruses including SARS-CoV-2, and could be used for the treatment of COVID-19 © Copyright © 2020 Yang, Lee, Hsu, Jan, Lin, Chang, Peng, Yang, Liang, Liao, Chao, Pang, Kao, Huang, Lin, Chang, Niu, Wu, Sytwu, Chen and Lee

The coronavirus (CoV) disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome CoV-2 (SARS-CoV-2) is a health threat worldwide. Viral main protease (Mpro, also called 3C‐like protease [3CLpro]) is a therapeutic target for drug discovery. Herein, we report that GC376, a broad-spectrum inhibitor targeting Mpro in the picornavirus-like supercluster, is a potent inhibitor for the Mpro encoded by SARS-CoV-2, with a half-maximum inhibitory concentration (IC50) of 26., The coronavirus (CoV) disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome CoV-2 (SARS-CoV-2) is a health threat worldwide. Viral main protease (Mpro, also called 3C‐like protease [3CLpro]) is a therapeutic target for drug discovery. Herein, we report that GC376, a broad-spectrum inhibitor targeting Mpro in the picornavirus-like supercluster, is a potent inhibitor for the Mpro encoded by SARS-CoV-2, with a half-maximum inhibitory concentration (IC50) of 26.4 ± 1.1 nM. In this study, we also show that GC376 inhibits SARS-CoV-2 replication with a half-maximum effective concentration (EC50) of 0.91 ± 0.03 μM. Only a small portion of SARS-CoV-2 Mpro was covalently modified in the excess of GC376 as evaluated by mass spectrometry analysis, indicating that improved inhibitors are needed. Subsequently, molecular docking analysis revealed that the recognition and binding groups of GC376 within the active site of SARS-CoV-2 Mpro provide important new information for the optimization of GC376. Given that sufficient safety and efficacy data are available for GC376 as an investigational veterinary drug, expedited development of GC376, or its optimized analogues, for treatment of SARS-CoV-2 infection in human is recommended.

Background The ongoing COVID-19 pandemic has caused more than 193,825 deaths during the past few months. A quick-to-be-identified cure for the disease will be a therapeutic medicine that has prior use experiences in patients in order to resolve the current pandemic situation before it could become worsening. Artificial intelligence (AI) technology is hereby applied to identify the marketed drugs with potential for treating COVID-19. Methods An AI platform was established to identify potential old drugs with anti-coronavirus activities by using two different learning databases; one consisted of the compounds reported or proven active against SARS-CoV, SARS-CoV-2, human immunodeficiency virus, influenza virus, and the other one containing the known 3C-like protease inhibitors. All AI predicted drugs were then tested for activities against a feline coronavirus in in vitro cell-based assay. These assay results were feedbacks to the AI system for relearning and thus to generate a modified AI model to search for old drugs again. Results After a few runs of AI learning and prediction processes, the AI system identified 80 marketed drugs with potential. Among them, 8 drugs (bedaquiline, brequinar, celecoxib, clofazimine, conivaptan, gemcitabine, tolcapone, and vismodegib) showed in vitro activities against the proliferation of a feline infectious peritonitis (FIP) virus in Fcwf-4 cells. In addition, 5 other drugs (boceprevir, chloroquine, homoharringtonine, tilorone, and salinomycin) were also found active during the exercises of AI approaches. Conclusion Having taken advantages of AI, we identified old drugs with activities against FIP coronavirus. Further studies are underway to demonstrate their activities against SARS-CoV-2 in vitro and in vivo at clinically achievable concentrations and doses. With prior use experiences in patients, these old drugs if proven active against SARS-CoV-2 can readily be applied for fighting COVID-19 pandemic.

Treatment of hyperglycemia with drugs that block renal glucose reabsorption via inhibition of sodium-dependent glucose cotransporter 2 (SGLT2) is a novel approach to diabetes management. In this study, twenty-seven aryl C-glycosides bearing a C=N/C−N linkage at the glucosyl C6 position were designed, synthesized and evaluated for their inhibitory activity against human SGLT2 (hSGLT2). Compounds with good hSGLT2 inhibition were further investigated to determine their selectivity over hSGLT1. Of these, five representative aryl C-glycosides were chosen for pharmacokinetic analysis. Oxime 2a was determined to have the most promising pharmacokinetic properties and was selected for in vivo glucosuria and plasma glucose level studies, which found it to exhibit comparable efficacy to dapagliflozin (1). Furthermore, 2a was not found to exhibit either significant cytotoxicity (CC50 > 50 μM) or human ether-a-go-go related gene (hERG) inhibition (2% inhibition at 10 μM). Taken together, these efforts culminated in the discovery of oxime 2a as a potential SGLT2 inhibitor.

Humans have two glutaminase genes, GLS (GLS1) and GLS2, each of which has two alternative transcripts: the kidney isoform (KGA) and glutaminase C (GAC) for GLS, and the liver isoform (LGA) and glutaminase B (GAB) for GLS2. Initial hit compound (Z)-5-((1-(4-bromophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)methylene)thiazolidine-2,4-dione (2), a thiazolidine-2,4-dione, was obtained from a high throughput screening of 40 000 compounds against KGA. Subsequently, a series of thiazolidine-2,4-dione derivatives was synthesized. Most of these were found to inhibit KGA and GAC with comparable activities, were less potent inhibitors of GAB, and were moderately selective for GLS1 over GLS2. The relationships between chemical structure, activity, and selectivity were investigated. The lead compounds obtained were found to (1) offer in vitro cellular activities for inhibiting cell growth, clonogenicity, and cellular glutamate production, (2) exhibit high concentrations of exposure in plasma by a pharmacokinetic study, and (3) reduce the tumor size of xenografted human pancreatic AsPC-1 carcinoma cells in mice.

A protocol for the microwave-assisted Heck coupling reaction of C-aryl glycosides and styrenes has been developed for the synthesis of mono- and bis(C-glycoside) stilbenes. This method exclusively provides C-glycoside trans-stilbenes in good yields. The Pd-catalyzed Heck coupling reaction was successfully applied to various functionalized C-glycosyl aryl iodides and various substituted styrenes to deliver several C-glycoside trans-stilbenes with high selectivity. The obtained C-glycosyl trans-stilbenes were also examined for human SGLT-2 inhibitory activity.

Suppression of glucose reabsorption through the inhibition of sodium-dependent glucose co-transporter 2 (SGLT2) is a promising therapeutic approach for the treatment of type 2 diabetes. To investigate the effect of C6-substitution on inhibition of SGLT2 by N-indolylglucosides, a small library of 6-triazole, 6-amide, 6-urea, and 6-thiourea N-indolylglycosides were synthesized and tested. A detailed structure-activity relationship (SAR) study culminated in the identification of 6-amide derivatives 6a and 6o as potent SGLT2 inhibitors, which were further tested for inhibitory activity against SGLT1. The data obtained indicated that 6a and 6o are mildly to moderately selective for SGLT2 over SGLT1. Both compounds were also evaluated in a urinary glucose excretion test and pharmacokinetic study; 6a was found capable of inducing urinary glucose excretion in normal SD rats.

Sodium-dependent glucose co-transporter 2 (SGLT2) inhibition has been demonstrated to efficiently control hyperglycemia via an insulin secretion-independent pathway. The unique mode of action eliminates the risk of hypoglycemia and makes SGLT2 inhibitors an attractive option for the treatment of type 2 diabetes. In a continuation of our previous studies on SGLT2 inhibitors bearing different sugar moieties, sixteen new N-glucosyl indole derivatives were designed, synthesized, and evaluated for their inhibitory activity against hSGLT2. Of these sixteen, acethydrazide-containing N-glucosyl indole 9d was found to be the most potent SGLT2 inhibitor, and caused a significant elevation in urine glucose excretion in rats at 50 mg/kg, relative to the vehicle control.

The function of the CXCR4/CXCL12 axis accounts for many disease indications, including tissue/nerve regeneration, cancer metastasis, and inflammation. Blocking CXCR4 signaling with its antagonists may lead to moving out CXCR4+ cell types from bone marrow to peripheral circulation. We have discovered a novel series of pyrimidine-based CXCR4 antagonists, a representative (i.e., 16) of which was tolerated at a higher dose and showed better HSC-mobilizing ability at the maximal response dose relative to the approved drug 1 (AMD3100), and thus considered a potential drug candidate for PBSCT indication. Docking compound 16 into the X-ray crystal structure of CXCR4 receptor revealed that it adopted a spider-like conformation striding over both major and minor subpockets. This putative binding mode provides a new insight into CXCR4 receptor–ligand interactions for further structural modifications.

Dengue virus (DENV) is a global health problem that affects approximately 3.9 billion people worldwide. Since safety concerns were raised for the only licensed vaccine, Dengvaxia, and since the present treatment is only supportive care, the development of more effective therapeutic anti-DENV agents is urgently needed. In this report, we identified a potential small-molecule inhibitor, BP34610, via cell-based high-throughput screening (HTS) of 12,000 compounds using DENV-2 reporter viruses. BP34610 reduced the virus yields of type 2 DENV-infected cells with a 50% effective concentration (EC50) and selectivity index value of 0.48 ± 0.06 μM and 197, respectively. Without detectable cytotoxicity, the compound inhibited not only all four serotypes of DENV but also Japanese encephalitis virus (JEV). Time-of-addition experiments suggested that BP34610 may act at an early stage of DENV virus infection. Sequencing analyses of several individual clones derived from BP34610-resistant viruses revealed a consensus amino acid substitution (S397P) in the N-terminal stem region of the E protein. Introduction of S397P into the DENV reporter viruses conferred an over 14.8-fold EC90 shift for BP34610. Importantly, the combination of BP34610 with a viral replication inhibitor, ribavirin, displayed synergistic enhancement of anti-DENV-2 activity. Our results identify an effective small-molecule inhibitor, BP34610, which likely targets the DENV E protein. BP34610 could be developed as an anti-flavivirus agent in the future.

Background Lung cancer has the highest rate of morbidity and mortality among various cancer types, being responsible for over 1.69 million deaths per year. Approximately 80–85% of the lung cancer patients diagnosed present non-small cell lung cancer (NSCLC), while 10–15% present small cell lung cancer (SCLC). Mutations in the epidermal growth factor receptor (EGFR) have been observed in ∼50% of patients, in particular, in East Asian NSCLC patients. The single-point mutation L858R (exon 21) and amino acids deletions in the tyrosine kinase (TK) domain (exon 19) constitute 90% of all EGFR-activating mutations. Methods We introduced an acrylamide group as a Michael acceptor, resulting in compound 2, which showed potent in vitroactivity in both wild and mutant EGFR kinases and potent anti-proliferative activity in HCC827 lung cancer cell line. In this work, we apply SBDD to guide the optimization of lead compound 2and perform a detailed structure-activity relationship (SAR) study to bring this drug candidate into the next development stage. Results We optimized the compound 2by scaffold hopping and by exploiting the potent inhibitory activity of various warhead groups. The results of the multi-objective optimization obtained the clinical candidate, compound 78 (DBPR112), which not only displayed a potent inhibitory activity against EGFR L858R/T790M double mutations, but also exhibited 10-fold potency better than 3rd generation inhibitor, osimertinib, against three EGFR and one HER2 exon 20 insertion mutations, since there are currently no EGFR-directed therapies approved specifically for the treatment of this mutation. Conclusions X-ray co-crystal study of EGFRWTKinase and compound 78 revealed the potential of future design for mutant-selective inhibitors. Finally, furanopyrimidine 78 was selected as a clinical candidate to conduct all preclinical experiments and is currently undergoing phase 1 clinical trial in Taiwan. Clinical trial identification NCT03246854. Legal entity responsible for the study The authors. Funding National Health Research Institutes, Taiwan. Disclosure All authors have declared no conflicts of interest.

The inhibition of FMS-like tyrosine kinase 3 (FLT3) activity using small-molecule inhibitors has emerged as a target-based alternative to traditional chemotherapy for the treatment of acute myeloid leukemia (AML). In this study, we report the use of structure-based virtual screening (SBVS), a computer-aided drug design technique for the identification of new chemotypes for FLT3 inhibition. For this purpose, homology modeling (HM) of the DFG-in FLT3 structure was carried using two template structures, including PDB ID: 1RJB (DFG-out FLT3 kinase domain) and PDB ID: 3LCD (DFG-in CSF-1 kinase domain). The modeled structure was able to correctly identify known DFG-in (SU11248, CEP-701 and PKC-412) and DFG-out (sorafenib, ABT-869 and AC220) FLT3 inhibitors, in docking studies. The modeled structure was then used to carry out SBVS of an HTS library of 125,000 compounds. The top scoring 97 compounds were tested for FLT3 kinase inhibition and two hits (BPR056, IC50 = 2.3 and BPR080, IC50 = 10.7 μM) were identified. Molecular dynamics simulation and density functional theory calculation suggest that BPR056 (MW: 325.32; cLogP: 2.48) interacted with FLT3 in a stable manner and could be chemically optimized to realize a drug-like lead in the future.

We have discovered a novel series of quinazoline-based CXCR4 antagonists. Of these, compound 19 mobilized CXCR4(+) cell types, including hematopoietic stem cells and endothelial progenitor cells, more efficiently than the marketed 1 (AMD3100) with subcutaneous administration at the same dose (6 mg/kg) in mice. This series of compounds thus provides a set of valuable tools to study diseases mediated by the CXCR4/SDF-1 axis, including myocardial infarction, ischemic stroke, and cancer metastasis. More importantly, treatment with compound 19 significantly lowered levels of blood urea nitrogen and serum creatinine in rats with renal ischemia-reperfusion injury, providing evidence for its therapeutic potential in preventing ischemic acute kidney injury. CXCR4 antagonists such as 19 might also be useful to increase circulating levels of adult stem cells, thereby exerting beneficial effects on damaged and/or inflamed tissues in diseases that currently are not treated by standard approaches.

Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer often associated with poor prognosis. Owing to the lack of therapeutic targets, patients with TNBC tend to rely on standard chemotherapy; however, chemo-resistance often develops in TNBC as a result of deregulated cell death control like in many other tumors. Long non-coding RNAs (lncRNAs) are transcripts longer than 200bp and have little or no protein-coding capacity. Although once considered as transcriptional noise, significant numbers of lncRNAs are now known as modulators of protein expression and functions and are implicated in a range of developmental processes and diseases. As many of them influence oncogenes and tumor suppressors in cancer, they represent excellent biomarkers as well as potential targets for therapy. In order to gain more insight on cell death regulation and to seek potential targets for TNBC, we employed an RNAi screen targeting 2231 lncRNAs in MDA-MB-231 TNBC cells. By using changes in cell metabolic activity (MTT assay) as readouts for primary screen and changes in cell number as confirmation, our unbiased screen identified two novel lncRNAs that drastically reduced cell proliferation when depleted. In addition to cell growth, the two lncRNAs also contribute to cancer cell migration and invasion. Interestingly, our gene profiling analyses and RNA immunoprecipitation studies show the two lncRNAs are involved in signaling cascades known to promote mammary tumorigenesis including EGF and β-catenin. We are now trying to delineate the detailed molecular mechanism(s) by which the two lncRNAs contribute to TNBC tumorigenesis. Together, our current results suggest a possibility for the two novel lncRNAs as drug targets in triple-negative breast cancer. Citation Format: Tse-Chun Kuo, Sheng-Chieh Hsu, Hui-Ju Chou, Pei-Shan Li, Szu-Huei Wu, Yen-Ling Yu, Jen-Shin Song, Hsing-Jien Kung. RNAi screen identified novel long non-coding RNAs involved in cell growth control, migration, and invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3502. doi:10.1158/1538-7445.AM2017-3502