snx-2112 and Disease-Models--Animal

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

As the endoplasmic reticulum paralogue of Hsp90, Grp94 chaperones a small set of client proteins associated with some diseases, including cancer, primary open-angle glaucoma, and inflammatory disorders. Grp94-selective inhibition has been a potential therapeutic strategy for these diseases. In this study, inspired by the conclusion that ligand-induced "Phe199 shift" effect is the structural basis of Grp94-selective inhibition, a series of novel Grp94 selective inhibitors incorporating "benzamide" moiety were developed, among which compound 54 manifested the most potent Grp94 inhibitory activity with an IC

Topics: Animals; Anti-Inflammatory Agents; Colitis, Ulcerative; Disease Models, Animal; Drug Discovery; HSP70 Heat-Shock Proteins; Inhibitory Concentration 50; Membrane Proteins; Mice; Structure-Activity Relationship

Heat shock protein 90 (Hsp90), a potential therapeutic target, has been widely recognized in vitro and in vivo in immunodeficient mice. Here, we aimed to evaluate the role of Hsp90 in an immunocompetent mouse model of esophageal squamous cell cancer (ESCC).. The carcinogen 4-nitroquinoline 1-oxide (4NQO) was used to induce ESCC in C57BL/6 mice. Cancer progression was analyzed through observation of appearance, hematoxylin-eosin staining, immunohistochemical detection, and terminal dUTP nick-end labeling analysis.. 4NQO led to the progressive appearance of preneoplastic and tumoral lesions in the esophagus, with 100 % incidence of ESCC in situ occurring only after 16 weeks of carcinogen exposure. Most of these lesions evolved spontaneously into highly invasive ESCC even after 4NQO withdrawal (weeks 16-22). Interestingly, there was marked upregulation of Hsp90 and its client proteins in tumoral lesions at 22 weeks. Hsp90 inhibition by intraperitoneal injection of SNX-2112 over the following 2 weeks downregulated AKT and cyclin D1 expression, leading to significant reduction in tumor incidence and prevention of ESCC progression. Moreover, SNX-2112 treatment decreased proliferating cell nuclear antigen expression and increased the number of apoptotic cells in ESCC tissues.. Our in vivo findings support the contribution of Hsp90 to ESCC progression, which was achieved by stimulating apoptosis and inhibition of cell proliferation, and provide a strong rationale for further evaluation of Hsp90 inhibitors for treating ESCC.

Topics: 4-Nitroquinoline-1-oxide; Animals; Carcinogens; Carcinoma, Squamous Cell; Cell Proliferation; Cell Transformation, Neoplastic; Cytoprotection; Disease Models, Animal; Disease Progression; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Female; Heterocyclic Compounds, 4 or More Rings; HSP90 Heat-Shock Proteins; Mice; Mice, Inbred C57BL

Inhibition of Hsp90 has emerged as a therapeutic strategy to target NSCLC subtypes, which are refractory to epidermal growth factor receptor (EGFR) inhibitor-based treatment. We report on a novel small molecule inhibitor of Hsp90, SNX-2112, and an orally bioavailable prodrug analog, SNX-5422. In cellular models of wild-type or mutant EGFR (L858R and T790M mutations), SNX-2112 alone and in combination with erlotinib inhibited EGF activation of pAKT(473) and pSTAT3(705). pERK1/2 and pS6 were also potently inhibited by similar treatments. SNX-2112 reduced EGF cross-talk and activation of the c-Met receptor by causing c-Met degradation. In NCI-H1975 xenograft models, SNX-5422 showed activity as a single agent and in combination with erlotinib resulted in prolonged animal survival at reduced compound concentrations relative to either compound alone. These results support the advanced evaluation of SNX-5422 as a treatment for non-small cell lung cancer (NSCLC), especially in cases where the cancer is driven by c-Met amplification or mutated EGFR forms that are resistant to EGFR inhibitors.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Disease Models, Animal; Drug Resistance, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Female; Heterocyclic Compounds, 4 or More Rings; HSP90 Heat-Shock Proteins; Humans; Lung Neoplasms; Mice; Mice, Nude; Quinazolines; Signal Transduction; Xenograft Model Antitumor Assays