ceritinib and Disease-Models--Animal

Immunotherapy (IT) and targeted therapy (TT) are both effective against melanoma, but their combination is frequently toxic. Here, we investigated whether the sequence of IT (anti-PD-1)→ TT (ceritinib-trametinib or dabrafenib-trametinib) was associated with improved antitumor responses in mouse models of

Topics: Animals; Antineoplastic Agents; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Disease Models, Animal; Female; Imidazoles; Immunotherapy; Melanoma; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Molecular Targeted Therapy; Monomeric GTP-Binding Proteins; Mutation; Oximes; Programmed Cell Death 1 Receptor; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidines; Pyrimidinones; Skin Neoplasms; Sulfones; T-Lymphocytes, Regulatory

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

Anaplastic lymphoma kinase (ALK) is an attractive therapeutic target for the treatment of non-small cell lung cancer (NSCLC). Within our ALK drug discovery program, we identified novel deuterated 2,4-diarylamino pyrimidine compounds as potent ALK inhibitors. The compound 11 showed better in vitro activity and in vivo efficacy with good pharmacokinetic profile. In vivo efficacy of compound 11 was better than standard drug ceritinib in NCI-H2228 xenograft mice model.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Disease Models, Animal; Heterografts; Mice; Protein Kinase Inhibitors

The efficacy of ALK inhibitors in patients with

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Cell Line, Tumor; Disease Models, Animal; Drug Resistance, Neoplasm; Heterografts; Humans; Mice, Nude; Neoplasm Transplantation; Neuroblastoma; Proto-Oncogene Proteins c-mdm2; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones