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Ouyang Q.,Computational Chemical Genomics Screening Center | Ouyang Q.,Chongqing Medical University | Nguyen K.N.,Washington University in St. Louis | Wang L.,Computational Chemical Genomics Screening Center | And 4 more authors.
Journal of Medicinal Chemistry | Year: 2014

Somatostatin receptor subtype 2 (sstr2) is a G-protein-coupled receptor (GPCR) that is overexpressed in neuroendocrine tumors. The homology model of sstr2 was built and was used to aid the design of new somatostatin analogues modified with phosphonate-containing cross-bridged chelators for evaluation of using them as PET imaging radiopharmaceuticals. The new generation chelators were conjugated to Tyr3-octreotate (Y3-TATE) through bioorthogonal, strain-promoted alkyne azide cycloaddition (SPAAC) to form CB-TE1A1P-DBCO-Y3- TATE (AP) and CB-TE1K1P-PEG4-DBCO-Y3-TATE (KP) in improved yields compared to standard direct conjugation methods of amide bond formation. Consistent with docking studies, the clicked bioconjugates showed high binding affinities to sstr2, with Kd values ranging from 0.6 to 2.3 nM. Selected isomers of the clicked products were used in biodistribution and PET/CT imaging. Introduction of the bulky dibenzocyclooctyne group in AP decreased clearance rates from circulation. However, the additional carboxylate group and PEG linker from the KP conjugate significantly improved labeling conditions and in vivo stability of the copper complex and ameliorated the slower pharmacokinetics of the clicked somatostatin analogues. © 2014 American Chemical Society.


Gao Y.,Institute of Hematology | Yang P.,Computational Chemical Genomics Screening Center | Yang P.,University of Pittsburgh | Shen H.,University of Pittsburgh | And 28 more authors.
Nature Communications | Year: 2015

Among cyclin-dependent kinase inhibitors that control the G1 phase in cell cycle, only p18 and p27 can negatively regulate haematopoietic stem cell (HSC) self-renewal. In this manuscript, we demonstrate that p18 protein is a more potent inhibitor of HSC self-renewal than p27 in mouse models and its deficiency promoted HSC expansion in long-term culture. Single-cell analysis indicated that deleting p18 gene favoured self-renewing division of HSC in vitro. Based on the structure of p18 protein and in-silico screening, we further identified novel smallmolecule inhibitors that can specifically block the activity of p18 protein. Our selected lead compounds were able to expand functional HSCs in a short-term culture. Thus, these putative small-molecule inhibitors for p18 protein are valuable for further dissecting the signalling pathways of stem cell self-renewal and may help develop more effective chemical agents for therapeutic expansion of HSC. © 2015 Macmillan Publishers Limited.


Myint K.-Z.,Carnegie Mellon University | Myint K.-Z.,Computational Chemical Genomics Screening Center | Myint K.-Z.,University of Pittsburgh | Wang L.,Computational Chemical Genomics Screening Center | And 5 more authors.
Molecular Pharmaceutics | Year: 2012

In this manuscript, we have reported a novel 2D fingerprint-based artificial neural network QSAR (FANN-QSAR) method in order to effectively predict biological activities of structurally diverse chemical ligands. Three different types of fingerprints, namely, ECFP6, FP2 and MACCS, were used in FANN-QSAR algorithm development, and FANN-QSAR models were compared to known 3D and 2D QSAR methods using five data sets previously reported. In addition, the derived models were used to predict GPCR cannabinoid ligand binding affinities using our manually curated cannabinoid ligand database containing 1699 structurally diverse compounds with reported cannabinoid receptor subtype CB2 activities. To demonstrate its useful applications, the established FANN-QSAR algorithm was used as a virtual screening tool to search a large NCI compound database for lead cannabinoid compounds, and we have discovered several compounds with good CB2 binding affinities ranging from 6.70 nM to 3.75 μM. To the best of our knowledge, this is the first report for a fingerprint-based neural network approach validated with a successful virtual screening application in identifying lead compounds. The studies proved that the FANN-QSAR method is a useful approach to predict bioactivities or properties of ligands and to find novel lead compounds for drug discovery research. © 2012 American Chemical Society.


Yang P.,Computational Chemical Genomics Screening Center | Yang P.,University of Pittsburgh | Wang L.,Computational Chemical Genomics Screening Center | Wang L.,University of Pittsburgh | And 14 more authors.
Journal of Medicinal Chemistry | Year: 2013

Cannabinoid receptors have gained increasing attention as drug targets for developing potential therapeutic ligands. Here, we report the discovery and optimization of triaryl sulfonamides as a novel series possessing significant CB2 receptor affinity and selectivity. Four sets of triaryl ligands were designed and synthesized for further structural modifications and led to the identification of eight compounds as potent and selective CB2 inverse agonists with high binding affinity (CB2Ki < 10 nM). Especially, compound 57 exhibited the strongest binding affinity on the CB2 receptor (CB2Ki of 0.5 nM) and the best selectivity over the CB1 receptor (selectivity index of 2594). Importantly, 57 also showed potent inhibitory activity on osteoclast formation, and it was confirmed by a cell viability assay that the inhibition effects were not derived from the cytotoxicity. Finally, 3D QSAR studies confirmed our SAR findings that three bulky groups play an important role for CB2 receptor binding affinity. © 2013 American Chemical Society.


Wang X.,Bengbu Medical College | Zhang J.-J.,Bengbu Medical College | Sun Y.-M.,Bengbu Medical College | Zhang J.,Bengbu Medical College | And 3 more authors.
Folia Biologica (Czech Republic) | Year: 2015

The purpose of the study was to evaluate the anti-tumour effects of triptolide (TPL) and of the combination of TPL and cisplatin (DDP) in DDP-resistant HNE1/DDP nasopharyngeal cancer (NPC) cells and to reveal the possible mechanisms. HNE1/DDP cells were treated with TPL and/or DDP. Cell proliferation was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and colony-forming assay; the combination index of the synergism between TPL and DDP was calculated. Cell morphological changes were observed under a microscope. Reactive oxygen species (ROS) and apoptosis rate were determined by flow cytome-try. 5,5',6,6'-tetrachloro-1,1',3,3'-tetrethyl benzimidalyl carbocyanine iodide (JC-1) staining was used to determine mitochondrial membrane potential (MMP). Protein expression was analysed by Western blot, including Bax, caspase-9, Bcl-2, Mcl-1. TPL had an obvious anti-tumour effect and exhibited synergistic cytotoxicity with DDP on DDP-resistant HNE1/DDP cells. TPL induced HNE1/DDP cell apoptosis via inducing ROS generation. This effect was abolished by the inhibitor of ROS, N-acetyl-L-cysteine (NAC). TPL alone or combined with DDP could lower MMP significantly. Western blot showed that TPL alone or in combination with DDP increased expression of Bax and caspase-9, but reduced expression of Bcl-2 and Mcl-1. We conclude that TPL could induce cell apoptosis and synergize with DDP by regulating ROS generation and mitochondrial pathways in HNE1/DDP cells. This indicates that TPL may be effective in DDP-resistant NPC, either alone or combined with DDP.


Ma C.,Computational Chemical Genomics Screening Center | Ma C.,University of Pittsburgh | Wang L.,Computational Chemical Genomics Screening Center | Wang L.,University of Pittsburgh | And 6 more authors.
Journal of Chemical Information and Modeling | Year: 2013

The cannabinoid receptor subtype 2 (CB2) is a promising therapeutic target for blood cancer, pain relief, osteoporosis, and immune system disease. The recent withdrawal of Rimonabant, which targets another closely related cannabinoid receptor (CB1), accentuates the importance of selectivity for the development of CB2 ligands in order to minimize their effects on the CB1 receptor. In our previous study, LiCABEDS (Ligand Classifier of Adaptively Boosting Ensemble Decision Stumps) was reported as a generic ligand classification algorithm for the prediction of categorical molecular properties. Here, we report extension of the application of LiCABEDS to the modeling of cannabinoid ligand selectivity with molecular fingerprints as descriptors. The performance of LiCABEDS was systematically compared with another popular classification algorithm, support vector machine (SVM), according to prediction precision and recall rate. In addition, the examination of LiCABEDS models revealed the difference in structure diversity of CB1 and CB2 selective ligands. The structure determination from data mining could be useful for the design of novel cannabinoid lead compounds. More importantly, the potential of LiCABEDS was demonstrated through successful identification of newly synthesized CB2 selective compounds. © 2013 American Chemical Society.


Ouyang Q.,Computational Chemical Genomics Screening Center | Ouyang Q.,University of Pittsburgh | Ouyang Q.,Chongqing Medical University | Tong Q.,Computational Chemical Genomics Screening Center | And 9 more authors.
ACS Medicinal Chemistry Letters | Year: 2013

An extensive exploration of the structure-activity relationship of a trisubstituted sulfonamide series led to the identification of 39, which is a potent and selective CB2 receptor inverse agonist [K i(CB2) = 5.4 nM, and Ki(CB1) = 500 nM]. The functional properties measured by cAMP assays indicated that the selected compounds were CB2 inverse agonists with high potency values (for 34, EC50 = 8.2 nM, and for 39, EC50 = 2.5 nM). Furthermore, an osteoclastogenesis bioassay indicated that trisubstituted sulfonamide compounds showed great inhibition of osteoclast formation. © 2013 American Chemical Society.


Zhang Z.,Bengbu Medical College | Li H.-M.,Bengbu Medical College | Zhou C.,Bengbu Medical College | Li Q.,Bengbu Medical College | And 8 more authors.
Journal of Experimental and Clinical Cancer Research | Year: 2016

Background: Hsp90 proteins are important therapeutic targets for many anti-cancer drugs in clinical trials. Geldanamycin (GA) was identified as the first natural inhibitor of Hsp90, increasing evidence suggests that GA was not a good choice for clinical trials. In this study, we investigated two new non-benzoquinone geldanamycin analogs of Hsp90 inhibitors, DHQ3 and 17-demethoxy-reblastatin (17-DR), to explore the molecular mechanisms of their anti-cancer activity in vivo and vitro. Methods: MTT and colony formation assays were used to measure cell viability. Flow cytometry, DAPI staining, ATP assay, electron microscopy, western blots, siRNAs transfection and immunofluorescence were used to determine the molecular mechanism of DHQ3- or 17-DR-induced different forms of death in human breast cancer MDA-MB-231 cells. Malachite green reagent was used to measure ATPase activity of the analogs. Results: DHQ3 and 17-DR presented efficiently inhibitory effect in MDA-MB-231 cell lines, and DHQ3 induced necroptosis by activation of the RIP1-RIP3-MLKL necroptosis cascade. And DHQ3-induced cell death was inhibited by a necroptosis inhibitor, necrostatin-1 (Nec-1), but not by a caspase inhibitor z-VAD-fmk. On the other hand, 17-DR induced apoptosis in MDA-MB-231 cells, indicating a caspase-dependent killing mechanism. We further demonstrated that down-regulation of RIP1 and RIP3 by siRNA protected against DHQ3 but not 17-DR induced cell death. These results were confirmed by electron microscopy. DHQ3 and 17-DR induced the degradation of Hsp90 client proteins, and they showed strong antitumor effects in MDA-MB-231 cell-xenografted nude mice. Conclusions: These findings supported that DHQ3 and 17-DR induce different forms of death in some cancer cell line via activation of different pathways. All of the results provided evidence for its anti-tumorigentic action with low hepatotoxicity in vivo, making them promising anti-breast cancer agents. © 2016 The Author(s).


PubMed | Computational Chemical Genomics Screening Center, Bengbu Medical College, University of Newcastle and Korea Research Institute of Bioscience and Biotechnology
Type: Journal Article | Journal: Journal of experimental & clinical cancer research : CR | Year: 2016

Hsp90 proteins are important therapeutic targets for many anti-cancer drugs in clinical trials. Geldanamycin (GA) was identified as the first natural inhibitor of Hsp90, increasing evidence suggests that GA was not a good choice for clinical trials. In this study, we investigated two new non-benzoquinone geldanamycin analogs of Hsp90 inhibitors, DHQ3 and 17-demethoxy-reblastatin (17-DR), to explore the molecular mechanisms of their anti-cancer activity in vivo and vitro.MTT and colony formation assays were used to measure cell viability. Flow cytometry, DAPI staining, ATP assay, electron microscopy, western blots, siRNAs transfection and immunofluorescence were used to determine the molecular mechanism of DHQ3- or 17-DR-induced different forms of death in human breast cancer MDA-MB-231 cells. Malachite green reagent was used to measure ATPase activity of the analogs.DHQ3 and 17-DR presented efficiently inhibitory effect in MDA-MB-231 cell lines, and DHQ3 induced necroptosis by activation of the RIP1-RIP3-MLKL necroptosis cascade. And DHQ3-induced cell death was inhibited by a necroptosis inhibitor, necrostatin-1 (Nec-1), but not by a caspase inhibitor z-VAD-fmk. On the other hand, 17-DR induced apoptosis in MDA-MB-231 cells, indicating a caspase-dependent killing mechanism. We further demonstrated that down-regulation of RIP1 and RIP3 by siRNA protected against DHQ3 but not 17-DR induced cell death. These results were confirmed by electron microscopy. DHQ3 and 17-DR induced the degradation of Hsp90 client proteins, and they showed strong antitumor effects in MDA-MB-231 cell-xenografted nude mice.These findings supported that DHQ3 and 17-DR induce different forms of death in some cancer cell line via activation of different pathways. All of the results provided evidence for its anti-tumorigentic action with low hepatotoxicity in vivo, making them promising anti-breast cancer agents.

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