incb-018424 and osimertinib

JAK1, JAK2, JAK3, and TYK2 belong to the JAK (Janus kinase) family. They play critical roles in cytokine signaling. Constitutive activation of JAK/STAT pathways is associated with a wide variety of diseases. Particularly, pSTAT3 is observed in response to the treatment with inhibitors of oncogenic signaling pathways such as EGFR, MAPK, and AKT and is associated with resistance or poorer response to agents targeting these pathways. Among the JAK family kinases, JAK1 has been shown to be the primary driver of STAT3 phosphorylation and signaling; therefore, selective JAK1 inhibition can be a viable means to overcome such treatment resistances. Herein, an account of the medicinal chemistry optimization from the promiscuous kinase screening hit

Topics: Acrylamides; Aniline Compounds; Animals; Cell Line, Tumor; Drug Design; Drug Discovery; Drug Screening Assays, Antitumor; Drug Synergism; ErbB Receptors; Female; Humans; Indoles; Janus Kinase 1; Mice, Nude; Molecular Structure; Protein Kinase Inhibitors; Structure-Activity Relationship; Xenograft Model Antitumor Assays