4-Amino-2-arylamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7-(8H)-ones as BCR kinase inhibitors for B lymphoid malignancies

Abstract

A new family of 4-aminopyrido[2,3-d]pyrimidines active against non-Hodgkin's lymphomas (NHLs) is described. Among these compounds, 19 inhibits the most upstream tyrosine kinases in the B cell receptor (BCR) signaling pathway which are involved in the mature B cell neoplasms. Thus, 19 showed antiproliferative activity at 24 h and 48 h against a panel of 20 NHLs cell lines with GI50 ranging from 1.3 to 6.9 μM at 24 h, and 1.4-7.2 μM at 48 h, being this effect related to a significant (20-90%) inhibition of the phosphorylation of the BCR-related kinases Btk, Syk, and Lyn. Most importantly, 19 was able to induce a 63% reduction in Rec-1 cell proliferation, which was significantly greater than the 31% and 3% blockade of proliferation observed after cell treatment with R406, a Syk inhibitor, and ibrutinib, a Btk inhibitor, respectively. The computational blind docking and ligand binding within the pockets of Btk, Syk and Lyn kinases showed that compound 19 presents the same kind of interactions of described cocrystallized inhibitors.

Keywords: 7-oxopyrido[2,3-d]pyrimidines; B-cell receptor; Kinases; Non-Hodgkin's lymphomas; Small molecule inhibitor.