cc-292 and Lymphoma--B-Cell

The BTK and JAK3 receptor tyrosine kinases are two validated and therapeutically amenable targets in the treatment of B-cell lymphomas. Here we report the identification of several classes of pyrimidine derivatives as potent BTK and JAK3 dual inhibitors. Among these molecules, approximately two thirds displayed strong inhibitory capacity at less than 10 nM concentration, and four compounds (7e, 7g, 7m and 7n) could significantly inhibit the phosphorylation of BTK and JAK3 enzymes at concentrations lower than 1 nM. Additionally, these pyrimidine derivatives also exhibited enhanced activity to block the proliferation of B-cell lymphoma cells compared with the representative BTK inhibitor ibrutinib. In particular, two structure-specific compounds 7b and 7e displayed stronger activity than reference agents in cell-based evaluation, with IC

Topics: Adult; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Humans; Janus Kinase 3; Leukocytes, Mononuclear; Lymphoma, B-Cell; Male; Mice; Mice, Inbred C57BL; Mice, SCID; Molecular Structure; Neoplasms, Experimental; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Structure-Activity Relationship