Research on antitumor effects of small molecule inhibitors of deubiquitinases: new progress and new ideas / 药学学报

The abnormality of ubiquitin proteasome pathway is an important factor leading to the imbalance of protein homeostasis. In this process, the deubiquitinase responsible for removing the ubiquitin chain of protein substrate is very important. Its abnormal activity or expression can cause the functional changes of key oncogenic/tumor suppressor proteins, which directly or indirectly lead to the occurrence, development and malignant evolution of tumors. Based on this, the discovery and research of small molecule inhibitors targeting deubiquitinases have become a hot field of anti-tumor candidate drugs. This review will focus on the regulatory effect and mechanism of ubiquitin proteasome pathway, especially deubiquitinase on tumor, introduce the application of deubiquitinase small molecule inhibitors in tumor treatment, and discuss the research status and latest progress of small molecule inhibitors, so as to provide ideas for the research of new anti-tumor strategies based on deubiquitinase.

Discovery of noveI EphB4 inhibitors based on pharmacophore modeIing and virtuaI screening techniques / 中国药科大学学报

The objective of this paper is to discover new potent inhibitors against EphB4 for cancer therapy via computer-aided drug design strategies including building 3D-QSAR models,virtual screening and molecular doc-king means.The first step is to generate pharmacophore models based on Catalyst/HypoGen algorithm.The best model,Hypo1,has the highest Correl value (0.96),the lowest RMS value (0.89),the closest total cost (101.26) to fixed cost (89.20),and the best Δcost (89.14).Subsequently,Hypo1 was subjected to test set validation and Fischer′s randomization verification and then was used as a 3D query to screen database.In order to further nar-row the number of hits,drug-likeness screening and molecular docking techniques were applied.Finally,23 novel molecules with diverse scaffolds were selected as possible candidates against EphB4 for further studies based on predicted activity analysis,docking scores,and binding modes analysis methods.

Progress in study of nitroimidazole as hypoxia imaging agents in tumor / 药学学报

Radionuclide hypoxia imaging has become an indispensable core of tumor diagnosis. Nitroimidazole derivatives have been extensively used as the hypoxia imaging agents in preclinical and clinical research. It is the key to design the ideal structure for promising agents. The type and quantity of nitroimidazole, the linker structure and chiral may have an impact on the imaging results. The characteristics of the imaging agents including single electron reduction potential (SERP), oil-water partition coefficient (log P) and pharmacokinetics are also the key factors. In this review, we highlight the factors for hypoxia imaging, providing clues for the structure design of new agents.

Advances on receptor tyrosine kinase inhibitors taking c-Met as anti-tumor target / 中国药科大学学报

@#c-Met receptor tyrosine kinase plays an important role in signaling pathways including cell proliferation, metabolism as well as tumorigenic growth, migration and angiogenesis. c-Met has emerged as an attractive target for cancer therapy. Moreover, the interactive cross-talk between c-Met signaling and several other signaling pathways underlies a key effect for resistance of anti-cancer drugs. Thus, multi-target inhibitors become a new approach to cancer therapy. This paper introduces the c-Met signaling pathway and the resistance of kinase inhibitors caused by the cross-talk between c-Met and other membrane receptors and then will reviews the progress of single-target and multi-target c-Met inhibitors.

Design and discovery of novel small-molecule inhibitor of CDK9 / 中国药理学通报

Aim To look for novel small-molecule inhibitors of CDK9 through structure-based virtual screening and biological activity determination.Methods Homology modeling of CDK9 was based on the 3-D structure of other cyclin-dependent kinase family members,and then virtual screening by DOCK(molecular docking)of database of small molecule was carried on.MTT method was used in inhibition of tumor cell growth in vitro,while Western blot was used for further study of molecular mechanisms.Results From the top 1000 compounds with the best DOCK energy score,27 compounds were selected for biological assay based on the diversity of chemical structure and functional group.12 of 27 selected compounds showed significantly inhibition activity on tumor cell proliferation,and only one compound in 12 with half-maximum inhibition concentration(IC50)values less than 20 ?mol?L-1 named C-21 was selected for further molecular mechanism study.The western blotting data showed C-21 compound could effectively inhibit CDK9 from phosphorylating large subunit C-terminal of RNA polymerase Ⅱ in a dose-dependent manner.Conclusions Through homology modeling,virtual screening by computer,determination of biological activity and experimental studies of molecular mechanism,a new promising lead compound targeted for CDK9 was found and confirmed.