Design, synthesis and biological evaluation of novel 2-phenyl pyrimidine derivatives as potent Bruton's tyrosine kinase (BTK) inhibitors

Abstract

BTK is an effective target for the treatment of B-cell malignant tumors and autoimmune diseases. In this work, a series of 2-phenyl pyrimidine derivatives were prepared and their preliminary <i>in vitro</i> activities on B-cell leukemia cells as well as the BTK enzyme were determined. The results showed that compound <b>11g</b> displayed the best inhibitory activity on BTK with an inhibition rate of 82.76% at 100 nM and excellent anti-proliferation activity on three B-cell leukemia lines (IC₅₀ = 3.66 μM, 6.98 μM, and 5.39 μM against HL60, Raji and Ramos, respectively). Besides, the flow cytometry analysis results indicated that <b>11g</b> inhibited the proliferation of the Raji cells in a dose- and time-dependent manner, and blocked the Ramos cells at the G0/G1 phase, which is in accordance with the positive control ibrutinib. The mechanism investigation demonstrated that <b>11g</b> could inhibit the phosphorylation of BTK and its downstream substrate phospholipase γ2 (PLCγ2). All these results showed that <b>11g</b> was a promising lead compound that merited further optimization as a novel class of BTK inhibitor for the treatment of B-cell lymphoblastic leukemia.