SKLB610: a novel potential inhibitor of vascular endothelial growth factor receptor tyrosine kinases inhibits angiogenesis and tumor growth in vivo.

Antagonizing angiogenesis-related receptor tyrosine kinase is a promising therapeutic strategy in oncology. In present study, we designed and synthesized a novel vascular endothelial growth factor receptor (VEGFR) inhibitor N-methyl-4-(4-(3-(trifluoromethyl) benzamido) phenoxy) picolinamide SKLB610 that potently suppresses human tumor angiogenesis. SKLB610 inhibited angiogenesis-related tyrosine kinase VEGFR2, fibroblast growth factor receptor 2 (FGFR2) and platelet-derived growth factor receptor (PDGFR) at rate of 97%, 65% and 55%, respectively, at concentration of 10μM in biochemical kinase assays.

Rapid and accurate assessment of seizure liability of drugs by using an optimal support vector machine method.

Drug-induced seizures are a serious adverse effect and assessment of seizure risk usually takes place at the late stage of drug discovery process, which does not allow sufficient time to reduce the risk by chemical modification. Thus early identification of chemicals with seizure liability using rapid and cheaper approaches would be preferable. In this study, an optimal support vector machine (SVM) modeling method has been employed to develop a prediction model of seizure liability of chemicals.

Combined SVM-based and docking-based virtual screening for retrieving novel inhibitors of c-Met.

Aberrant c-Met activation has been demonstrated to be implicated in tumorigenesis and anti-cancer drug resistance. Discovery of c-Met inhibitors has attracted much attention in recent years. In this study, a support vector machine (SVM) classification model that discriminates c-Met inhibitors and non-inhibitors was first developed.

SKLB1002, a novel potent inhibitor of VEGF receptor 2 signaling, inhibits angiogenesis and tumor growth in vivo.

Purpose: VEGF receptor 2 (VEGFR2) inhibitors, as efficient antiangiogenesis agents, have been applied in the cancer treatment. However, currently most of these anticancer drugs suffer some adverse effects. Discovery of novel VEGFR2 inhibitors as anticancer drug candidates is still needed.

The Therapeutic Target Database: an internet resource for the primary targets of approved, clinical trial and experimental drugs.

Increasing numbers of proteins, nucleic acids and other molecular entities have been explored as therapeutic targets. A challenge in drug discovery is to decide which targets to pursue from an increasing pool of potential targets, given the fact that few innovative targets have made it to the approval list each year. Knowledge of existing drug targets (both approved and within clinical trials) is highly useful for facilitating target discovery, selection, exploration and tool development.

Discovery of novel Pim-1 kinase inhibitors by a hierarchical multistage virtual screening approach based on SVM model, pharmacophore, and molecular docking.

In this investigation, we describe the discovery of novel potent Pim-1 inhibitors by employing a proposed hierarchical multistage virtual screening (VS) approach, which is based on support vector machine-based (SVM-based VS or SB-VS), pharmacophore-based VS (PB-VS), and docking-based VS (DB-VS) methods. In this approach, the three VS methods are applied in an increasing order of complexity so that the first filter (SB-VS) is fast and simple, while successive ones (PB-VS and DB-VS) are more time-consuming but are applied only to a small subset of the entire database. Evaluation of this approach indicates that it can be used to screen a large chemical library rapidly with a high hit rate and a high enrichment factor.

Foxo1 mediates insulin-like growth factor 1 (IGF1)/insulin regulation of osteocalcin expression by antagonizing Runx2 in osteoblasts.

In this study, we determined the molecular mechanisms whereby forkhead transcription factor Foxo1, a key downstream signaling molecule of insulin-like growth factor 1 (IGF1)/insulin actions, regulates Runx2 activity and expression of the mouse osteocalcin gene 2 (Bglap2) in osteoblasts in vitro. We showed that Foxo1 inhibited Runx2-dependent transcriptional activity and osteocalcin mRNA expression and Bglap2 promoter activity in MC-4 preosteoblasts. Co-immunoprecipitation assay showed that Foxo1 physically interacted with Runx2 via its C-terminal region in osteoblasts or when co-expressed in COS-7 cells.

Synthesis and biological evaluation of novel 5-benzylidenethiazolidine-2,4-dione derivatives for the treatment of inflammatory diseases.

Twenty-two compounds based on thiazolidine-2,4-dione moiety were synthesized and evaluated for the inhibitory potency on the production of nitric oxide (NO), inducible nitric oxide synthase (iNOS) activity, and the generation of prostaglandin E(2) (PEG(2)). (Z)-N-(3-chlorophenyl)-2-(4-((2,4-dioxothiazolidin-5-ylidene) methyl) phenoxy) acetamide (3I), superior to the commercial anti-inflammatory drug indomethacin, significantly inhibited iNOS activity (IC(50) = 8.66 μM), iNOS-mediated NO, and cyclooxygenase (COX)-2-derived PGE(2) production (IC(50) = 4.

Discovery of novel mGluR1 antagonists: a multistep virtual screening approach based on an SVM model and a pharmacophore hypothesis significantly increases the hit rate and enrichment factor.

Development of glutamate non-competitive antagonists of mGluR1 (Metabotropic glutamate receptor subtype 1) has increasingly attracted much attention in recent years due to their potential therapeutic application for various nervous disorders. Since there is no crystal structure reported for mGluR1, ligand-based virtual screening (VS) methods, typically pharmacophore-based VS (PB-VS), are often used for the discovery of mGluR1 antagonists. Nevertheless, PB-VS usually suffers a lower hit rate and enrichment factor.

Synthesis, structure-activity relationships and preliminary antitumor evaluation of benzothiazole-2-thiol derivatives as novel apoptosis inducers.

A series of novel benzothiazole-2-thiol derivatives were synthesized, and their anti-proliferative activities on HepG2 and MCF-7 cells were investigated. Most compounds had inhibitory effects on cell growth, and some of them were more effective than cisplatin. Compounds 6m and 6t displayed good inhibitory activities against a panel of different types of human cancer cell lines, with IC(50) values in the low micromolar range.

Integrated computational model of cell cycle and checkpoint reveals different essential roles of Aurora-A and Plk1 in mitotic entry.

Understanding the regulation of mitotic entry is one of the most important goals of modern cell biology, and computational modeling of mitotic entry has been a subject of several recent studies. However, there are still many regulation mechanisms that remain poorly characterized. Two crucial aspects are how mitotic entry is controlled by its upstream regulators Aurora-A and Plk1, and how mitotic entry is coordinated with other biological events, especially G2/M checkpoint.

Synthesis and biological evaluation of oleanolic acid derivatives as inhibitors of protein tyrosine phosphatase 1B.

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator in the process of insulin signaling and a promising drug target for diabetes and obesity. Derivatives of oleanolic acid were synthesized and evaluated as PTP1B inhibitors. Several derivatives exhibited moderate to good inhibitory activities against PTP1B, with 25f displaying the most promising inhibition (IC(50) = 3.

MAPK phosphatase-3 promotes hepatic gluconeogenesis through dephosphorylation of forkhead box O1 in mice.

Insulin resistance results in dysregulated hepatic gluconeogenesis that contributes to obesity-related hyperglycemia and progression of type 2 diabetes mellitus (T2DM). Recent studies show that MAPK phosphatase-3 (MKP-3) promotes gluconeogenic gene transcription in hepatoma cells, but little is known about the physiological role of MKP-3 in vivo. Here, we have shown that expression of MKP-3 is markedly increased in the liver of diet-induced obese mice.

Antitumor and antimetastatic activities of chloroquine diphosphate in a murine model of breast cancer.

Metastatic breast cancers are hard to treat and almost always fatal. Chloroquine diphosphate, a derivative of quinine, has long been used as a potent and commonly used medicine against different human diseases. We therefore investigated the effects of chloroquine diphosphate on a highly metastatic mouse mammary carcinoma cell line.

Novel thienopyridine derivatives as specific anti-hepatocellular carcinoma (HCC) agents: synthesis, preliminary structure-activity relationships, and in vitro biological evaluation.

Novel thienopyridine derivatives 1b-1r were synthesized, based on a hit compound 1a that was found in a previous cell-based screening of anticancer drugs. Compounds 1a-1r have the following features: (1) their anticancer activity in vitro was first reported by our group. (2) The most potent analog 1g possesses hepatocellular carcinoma (HCC)-specific anticancer activity.

Design and synthesis of 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles and pyrazolo[3,4-b]pyridines for Aurora-A kinase inhibitors.

Two series of 3-aminopyrazole compounds including 24 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles and 16 pyrazolo[3,4-b]pyridines were synthesized and evaluated against HCT116, A549, and A2780 tumor cell lines. Among them, three compounds were found to have the ideal anti-proliferative activities in vitro. Docking experiments showed that the novel pyrazolo[3,4-b]pyridines share the similar interaction mode with Aurora-A kinase as PHA739358.

Pharmacophore modeling and applications in drug discovery: challenges and recent advances.

Pharmacophore approaches have become one of the major tools in drug discovery after the past century's development. Various ligand-based and structure-based methods have been developed for improved pharmacophore modeling and have been successfully and extensively applied in virtual screening, de novo design and lead optimization. Despite these successes, pharmacophore approaches have not reached their expected full capacity, particularly in facing the demand for reducing the current expensive overall cost associated with drug discovery and development.

PhDD: a new pharmacophore-based de novo design method of drug-like molecules combined with assessment of synthetic accessibility.

This account describes a new pharmacophore-based de novo design method of drug-like molecules (PhDD). The method PhDD first generates a set of new molecules that completely conform to the requirements of a given pharmacophore model, followed by a series of assessments to the generated molecules, including assessments of drug-likeness, bioactivity, and synthetic accessibility. PhDD is tested on three typical examples, namely, pharmacophore hypotheses of histone deacetylase (HDAC), cyclin-dependent kinase 2 (CDK2) and HIV-1 integrase (IN) inhibitors.

Steered molecular dynamics simulations reveal the likelier dissociation pathway of imatinib from its targeting kinases c-Kit and Abl.

Development of small molecular kinase inhibitors has recently been the central focus in drug discovery. And type II kinase inhibitors that target inactive conformation of kinases have attracted particular attention since their potency and selectivity are thought to be easier to achieve compared with their counterpart type I inhibitors that target active conformation of kinases. Although mechanisms underlying the interactions between type II inhibitors and their targeting kinases have been widely studied, there are still some challenging problems, for example, how type II inhibitors associate with or dissociate from their targeting kinases.

Discovery of (Z)-5-(4-methoxybenzylidene)thiazolidine-2,4-dione, a readily available and orally active glitazone for the treatment of concanavalin A-induced acute liver injury of BALB/c mice.

A large amount of evidence suggests that monocytes/macrophages infiltration is implicated in a variety of inflammatory diseases including acute liver injury. Monocyte chemoattractant protein 1 (MCP-1) plays a crucial role in the process of macrophages recruitment. We herein presented a small-molecule library and a feasible quick screening method of evaluating potency of inhibition of chemotaxis of RAW264.

[The feasibility of application of reverse docking method to the selectivity studies of protein kinase inhibitors].

This investigation is to explore the feasibility of applying reverse docking method to the selectivity studies of protein kinase inhibitors. Firstly, a database that consists of 422 protein kinase structures was established through collecting the reported crystal structures or homology modeling. Then a reverse docking based method of protein kinase target screening was established, followed by the optimization of related parameters and scoring functions.

Pharmacophore modeling and virtual screening for the discovery of new transforming growth factor-beta type I receptor (ALK5) inhibitors.

Inhibitors of transforming growth factor-beta Type I Receptor (ALK5) have been thought as potential drugs for the treatment of fibrosis and cancer and a considerable number of ALK5 inhibitors have been reported recently. In order to clarify the essential structure-activity relationship for the known ALK5 inhibitors as well as identify new lead compounds against ALK5, 3D pharmacophore models have been established based on the known ALK5 inhibitors. The best pharmacophore model, Hypo1, was used as a 3D search query to perform a virtual screening.

Semi-synthesis and anti-proliferative activity evaluation of novel analogues of Honokiol.

A series of honokiol analogues were synthesized by modifying the 5- and/or 3'-position(s) of honokiol to assess their anti-tumor effects. Some compounds exerted more potent anti-proliferative activities than those of honokiol on K562 leukemia cells, A549 alveolar basal epithelial cells, SPC-A1 adenocarcinoma cells and A2780 human ovarian carcinoma cells in vitro. Compounds 2b, 3a, and 3c displayed most potent anti-proliferative activities against these tested cell strains and their anti-drug resistance effects were evaluated in vitro on cisplatin-resistant A2780 human ovarian carcinoma cells.

Pharmacophore modeling and virtual screening studies of checkpoint kinase 1 inhibitors.

In this study, chemical feature-based 3-dimensional (3D) pharmacophore models of Checkpoint kinase 1 (Chk1) inhibitors were developed based on the known inhibitors of Chk1. The best pharmacophore model Hypo1 was characterized by the best correlation coefficient (0.9577), and the lowest root mean square deviation (0.