Garrison K.,Earle A Chiles Research Institute |
Hahn T.,Earle A Chiles Research Institute |
Lee W.-C.,Shanghai Medicilon Inc. |
Ling L.E.,Biogen Idec |
And 2 more authors.
Cancer Immunology, Immunotherapy | Year: 2012
Effective tumor immunotherapy may require not only activation of anti-tumor effector cells, but also abrogation of tumor-mediated immunosuppression. The cytokine TGF-β, is frequently elevated in the tumor microenvironment and is a potent immunosuppressive agent and promoter of tumor metastasis. OX40 (CD134) is a member of the TNF-α receptor superfamily and ligation by agonistic antibody (anti-OX40) enhances effector function, expansion, and survival of activated T cells. In this study, we examined the therapeutic efficacy and antitumor immune response induced by the combination of a small molecule TGF-β signaling inhibitor, SM16, plus anti-OX40 in the poorly immunogenic, highly metastatic, TGF-β-secreting 4T1 mammary tumor model. Our data show that SM16 and anti-OX40 mutually enhanced each other to elicit a potent anti-tumor effect against established primary tumors, with a 79% reduction in tumor size, a 95% reduction in the number of metastatic lung nodules, and a cure rate of 38%. This positive treatment outcome was associated with a 3.2-fold increase of tumor-infiltrating, activated CD8+ T cells, an overall accumulation of CD4+and CD8+ T cells, and an increased tumor-specific effector T cell response. Complete abrogation of the therapeutic effect in vivo following depletion of CD4+ and CD8+ T cells suggests that the anti-tumor efficacy of SM16+ anti-OX40 therapy is T cell dependent. Mice that were cured of their tumors were able to reject tumor re-challenge and manifested a significant tumor-specific peripheral memory IFN-γ response. Taken together, these data suggest that combining a TGF-β signaling inhibitor with anti-OX40 is a viable approach for treating metastatic breast cancer. © Springer-Verlag 2011. Source
Yin Z.,China Pharmaceutical University |
Yin Z.,University of Wollongong |
Song Y.,Shanghai University |
Rehse P.H.,Shanghai Medicilon Inc.
ACS Chemical Biology | Year: 2013
Phosphorylation-dependent protein-protein interaction has rarely been targeted in medicinal chemistry. Thymoquinone, a naturally occurring antitumor agent, disrupts prephosphorylated substrate recognition by the polo-box domain of polo-like kinase 1, a key mitotic regulator responsible for various carcinogenesis when overexpressed. Here, crystallographic studies reveal that the phosphoserine/phosphothreonine recognition site of the polo-box domain is the binding pocket for thymoquinone and its analogue poloxime. Both small molecules displace phosphopeptides bound with the polo-box domain in a slow but noncovalent binding mode. A conserved water bridge and a cation-π interaction were found as their competition strategy against the phosphate group. This mechanism sheds light on small-molecule intervention of phospho-recognition by the polo-box domain of polo-like kinase 1 and other phospho-binding proteins in general. © 2012 American Chemical Society. Source
Zhang C.,Merck And Co. |
Ondeyka J.,Merck And Co. |
Herath K.,Merck And Co. |
Jayasuriya H.,Merck And Co. |
And 9 more authors.
Journal of Natural Products | Year: 2011
Platensimycin (1a) and platencin (2) are inhibitors of FabF and FabF/H bacterial fatty acid synthase. The discovery of natural congeners is an approach that can render a better understanding of the structure-function relationships of complex natural products. The isolation and structure elucidation of nine new congeners (11-20) of platensimycin and platencin are described from a fermentation broth of Streptomyces platensis. These hydroxylated congeners are likely derived by cytochrome P450 oxidation of the terpenoid units post-cyclization. Polar groups in the terpenoid portion of the molecule produce negative interactions with the hydrophobic pocket of FabF, resulting in poor activities. However, the discovery of these compounds serves an important purpose, not only to understand structure-function relationships, which cannot be easily accessed by chemical modification, but also to provide access to compounds that could be used for structural identification/confirmation of the oxidative trace metabolites produced in vivo during animal experiments. © 2011 The American Chemical Society and American Society of Pharmacognosy. Source
Zhou Y.,China Pharmaceutical University |
Jianhua C.,China Pharmaceutical University |
Rehse P.H.,Shanghai Medicilon Inc.
Journal of Medical Colleges of PLA | Year: 2010
Objective: To provide a kinetic model(s) and reveal the mechanism of thymoquinone and Poloxin blocking an emerging anti-cancer target, human Polo-like kinase 1 (hPlk1) Polo-box domain (PBD). Methods: The binding kinetics was determined by using a fluorescence polarization based assay. The putative mechanism was examined with a competition test. Results: Thymoquinone follows a one-step binding with an association rate constant (k1) of 6.635×103 L·mol-1·min-1. Poloxin fit a two-step binding with a dissociation constant (Ki) of 118 μmol/L for the intermediate complex and its isomerization rate (k4) of 0.131 5 min-1 to form an irreversible adduct. No significant dissociation was observed for either ligand up to 13 h. The inhibitors responded insignificantly to the presence of Michael donors as hPlk1-PBD competitors. Conclusion: Thymoquinone and Poloxin are slow-tight ligands to the hPlk1-PBD with kinetic models distinct from each other. Michael addition as the mechanism is excluded. © 2010 The Editorial Board of Journal of Medical Colleges of PLA. Source
Zhu J.,Fudan University |
Zhu J.,Shanghai Medicilon Inc. |
Yang Q.,Fudan University |
Dai D.,Fudan University |
Huang Q.,Fudan University
Journal of the American Chemical Society | Year: 2013
To better understand the structural origins of inhibitor selectivity of human phosphodieasterase families (PDEs 1-11), here we report the X-ray crystal structure of PDE2 in complex with a highly selective, nanomolar inhibitor (BAY60-7550) at 1.9 Å resolution, and the structure of apo PDE2 at 2.0 Å resolution. The crystal structures reveal that the inhibitor binds to the PDE2 active site by using not only the conserved glutamine-switch mechanism for substrate binding, but also a binding-induced, hydrophobic pocket that was not reported previously. In silico affinity profiling by molecular docking indicates that the inhibitor binding to this pocket contributes significantly to the binding affinity and thereby improves the inhibitor selectivity for PDE2. Our results highlight a structure-based design strategy that exploits the potential binding-induced pockets to achieve higher selectivity in the PDE inhibitor development. © 2013 American Chemical Society. Source