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Abstract: 8-Chloro-cAMP (8-Cl-cAMP) and its metabolite 8-chloro-adenosine (8-Cl-Ado) inhibit cell growth by 8-Cl-Ado-converted 8-Cl-ATP that targets cell-cycle control and RNA metabolism. However, the cell-cycle checkpoint pathways remain to be identified. Recent studies have shown that 8-Cl-cAMP administration and 8-Cl-Ado exposure may damage chromosomal DNA in vivo and in vitro. In this study, we demonstrate that 8-Cl-Ado-induced DNA damage activates G2/M phase checkpoint, which is associated with ATM-activated CHK1-CDC25C-CDC2 pathway joined by BRCA1-CHK1 branch in apoptosis-resistant human myelocytic leukemia K562 (p53-null) cells. Inhibition of CHK1 kinase by Gö6976, an inhibitor of CHK1 activity, can promote DNA damage and lead to the activation of CHK2, converting G2/M checkpoint into intra-S-phase checkpoint in which two parallel branches, the ATM-CHK2-CDC25A-CDK2 and the ATM-NBS1/SMC1 cascades, are involved. These observations may provide aid in better understanding of the mechanisms of 8-Cl-cAMP and 8-Cl-Ado actions and in potential design of the combined therapy. [Copyright &y& Elsevier]

Presents information on the measurement of cellular lactate dehydrogenase (LDH) release during metabolic inhibition, as a monitor of sarcolemmal integrity as affected by variation of external pH (pHe) and Ca2+ concentration ([Ca2+]e). Information on the relationship between pHe and [(Ca2+}e; Increase of cell lysis in graded manner.

Abstract: 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. The test results demonstrate that PhDD is able to generate molecules with novel structures but having similar biological functions with existing inhibitors. The validity of PhDD together with its ability of assessing synthetic accessibility makes it a useful tool in rational drug design. [Copyright &y& Elsevier]

Protein arginine methyltransferase 5 (PRMT5) is an important protein arginine methyltransferase that catalyzes the symmetric dimethylation of arginine resides on histones or non-histone substrate proteins. It has been thought as a promising target for many diseases, particularly cancer. Despite the potential applications of PRMT5 inhibitors in cancer treatment, very few of PRMT5i have been publicly reported. In this investigation, virtual screening and structure-activity relationship studies were carried out to discover novel PRMT5i, which finally led to the identification of a number of new PRMT5i. The most active compound, P5i-6, exhibited a considerable inhibitory potency against PRMT5 with an IC50 value of 0.57 μ m, and a high selectivity for PRMT5 against other tested PRMTs. It displayed a very good antiviability activity against two colorectal cancer cell lines, HT-29 and DLD-1, and one hepatic cancer cell line, HepG2, in a sensitivity assay against 36 different cancer cell lines. Western blot assays indicated that P5i-6 selectively inhibited the symmetric dimethylations of H4R3 and H3R8 in DLD-1 cells. Overall, P5i-6 could be used as a chemical probe to investigate new functions of PRMT5 in biology and also served as a good lead compound for the development of new PRMT5-targeting therapeutic agents. [ABSTRACT FROM AUTHOR]

Herein we report the discovery of a series of new KDM5A inhibitors. A three-dimensional (3D) structure model of KDM5A jumonji domain was firstly established based on homology modeling. Molecular docking-based virtual screening was then performed against commercial chemical databases. A number of hit compounds were retrieved. Further structural optimization and structure–activity relationship (SAR) analysis were carried out to the most active hit compound, 9 (IC 50 : 2.3 μM), which led to the discovery of several new KDM5A inhibitors. Among them, compound 15e is the most potent one with an IC 50 value of 0.22 μM against KDM5A. This compound showed good selectivity for KDM5A and considerable ability to suppress the demethylation of H3K4me3 in intact cells. Compound 15e could be taken as a good lead compound for further studies. [ABSTRACT FROM AUTHOR]

Despite a potential application of PRMT1 inhibitors in cancer treatment, very few of PRMT1 inhibitors have been reported. To obtain novel potent PRMT1 inhibitors, structure optimizations towards a hit compound, 4-((6-chloro-5-nitropyrimidin-4-yl)amino)benzimidamide, were carried out. A series of 4-((5-nitropyrimidin-4-yl)amino)benzimidamide derivatives were synthesized. Structure–activity relationship analysis led to the discovery of a number of PRMT1 inhibitors. The most potent compound corresponds to compound 6d , which showed an IC 50 value of 2.0 μM against PRMT1. This compound also displayed a considerable anti-proliferative activity against three tumor cell lines, DLD-1, T24 and SH-SY-5Y, with IC 50 values of 4.4 μM, 13.1 μM and 11.4 μM, respectively. [ABSTRACT FROM AUTHOR]

Abstract: Aberrant activation of casein kinase 1 (CK1) has been demonstrated to be implicated in the pathogenesis of cancer and various central nervous system disorders. Discovery of CK1 inhibitors has thus attracted much attention in recent years. In this account, we describe the discovery of N6-phenyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine derivatives as novel CK1 inhibitors. An optimal common-feature pharmacophore hypothesis, termed Hypo2, was firstly generated, followed by virtual screening using Hypo2 against several chemical databases. One of the best hit compounds, N6-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine, was chosen for the subsequent hit-to-lead optimization under the guide of Hypo2, which led to the discovery of a new lead compound (1-(3-(3-amino-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)phenyl)-3-(3-chloro-4-fluorophenyl)urea) that potently inhibits CK1 with an IC50 value of 78 nM. [Copyright &y& Elsevier]

Abstract: 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. Evaluation through screening a test set indicates that combined SVM-based and docking-based virtual screening (SB/DB-VS) considerably increases hit rate and enrichment factor compared with the individual methods. Thus the combined SB/DB-VS approach was adopted to screen PubChem, Specs, and Enamine for c-Met inhibitors. 75 compounds were selected for in vitro assays. Eight compounds display a good inhibitory potency against c-Met. Five of them are found to have novel scaffolds, implying a good potential for further chemical modification. [Copyright &y& Elsevier]

Abstract: 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 IC50 values in the low micromolar range. Further biological evaluation indicated that 6m induced apoptosis in HepG2 cancer cells. Structure–activity relationships were also proposed. [Copyright &y& Elsevier]

Abstract: Inhibitors of transforming growth factor-β 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. The hit compounds were subsequently subjected to filtering by Lipinski''s rule of five and docking studies to refine the retrieved hits. Finally a total of 100 compounds were obtained and some of them were selected for further in vitro and in vivo assay studies. [Copyright &y& Elsevier]

Abstract: Pharmacophore models of Polo-like kinase-1 (PLK1) inhibitors have been established by using the HipHop and HypoGen algorithms implemented in the Catalyst software package. The best quantitative pharmacophore model, Hypo1, which has the highest correlation coefficient (0.9895), consists of one hydrogen bond acceptor, one hydrogen bond donor, one hydrophobic feature, and one hydrophobic aliphatic feature. Hypo1 was further validated by test set and cross validation method. Then Hypo1 was used as a 3D query to screen several databases including Specs, NCI, Maybridge, and Chinese Nature Product Database (CNPD). The hit compounds were subsequently subjected to filtering by Lipinski’s rule of five and docking study to refine the retrieved hits and as a result to reduce the rate of false positive. Finally, a total of 20 compounds were selected and have been shifted to in vitro and in vivo studies. As far as we know, this is the first report on the pharmacophore modeling even the first publicly reported virtual screening study of PLK1 inhibitors. [Copyright &y& Elsevier]

Abstract: Development of fatty acid synthase (FAS) inhibitors has increasingly attracted much attention in recent years due to their potential therapeutic use in obesity and cancers. In this investigation, pharmacophore modeling based on the first crystal structure of human KS domain of FAS was carried out. The established pharmacophore model was taken as a 3D query for retrieving potent FAS inhibitors from the chemical database Specs. Docking study was further carried out to refine the obtained hit compounds. Finally, a total of 28 compounds were selected based on the ranking order and visual examination, which were first evaluated by a cell line-based assay. Seven compounds that have good inhibition activity against two FAS overexpressing cancer cell lines were further evaluated by an enzyme-based assay. One compound with a new chemical scaffold was found to have low micromolar inhibition potency against FAS, which has been subjected to further chemical structural modification. [Copyright &y& Elsevier]