Synthesis and Biological Evaluation of B-Cell Lymphoma 6 Inhibitors of N-Phenyl-4-pyrimidinamine Derivatives Bearing Potent Activities against Tumor Growth

Abstract

The transcriptional repressor B-cell lymphoma 6 (BCL6) is frequently misregulated in diffuse large B-cell lymphoma (DLBCL) and has emerged as an attractive drug target for the treatments of lymphoma. In this article, a series of N-phenyl-4-pyrimidinamine derivatives were designed and synthesized as potent BCL6 inhibitors by optimizing hit compound N 4-(3-chloro-4-methoxyphenyl)-N 2-isobutyl-5-fluoro-2,4-pyrimidinediamine on the basis of the structure–activity relationship. Among them, compound 14j displayed the most potent activities, which significantly blocked the interaction of BCL6 with its corepressors, reactivated BCL6 target genes in a dose-dependent manner, and had better effects compared with the two positive controls. Further studies indicated that a low dose of 14j could effectively inhibit germinal center formation. More importantly, 14j not only showed potent inhibition of DLBCL cell proliferation in vitro but also strongly suppressed the growth of DLBCL in vivo.

GSK137, a potent small-molecule BCL6 inhibitor with in vivo activity, suppresses antibody responses in mice

“…It was suggested that proliferation and survival of DLBCL cell lines expressing BCL6 are suppressed by small-molecule and peptide inhibitors of BCL6 ( 8 , 9 ), but subsequent results have been mixed with some classes of inhibitor potently repressing DLBCL cell lines ( 37 , 41 , 42 ), whereas others show little effect ( 38 , 39 , 40 ). We selected three BCL6-expressing DLBCL model cell lines (Farage, Karpas422, and ULA) as well as a B-ALL model (VAL) to investigate the effects of GSK137.…”

“…Others have subsequently developed different peptides to block co-repressor binding ( 34 , 35 ) but the functional importance of the peptide binding site in the lateral groove of the BCL6 BTB-POZ domain prompted work to explore the development of small molecule inhibitors. A number of small molecule inhibitors with a variety of chemical structures have now been described ( 9 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ) and some of these are able to suppress DLBCL cell line proliferation and survival ( 9 , 36 , 41 , 42 ). A small number of these compounds show some in vivo efficacy in repressing normal mouse antibody responses ( 37 ) or growth of cell line xenografts ( 37 , 38 ).…”

“…A number of small molecule inhibitors with a variety of chemical structures have now been described ( 9 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ) and some of these are able to suppress DLBCL cell line proliferation and survival ( 9 , 36 , 41 , 42 ). A small number of these compounds show some in vivo efficacy in repressing normal mouse antibody responses ( 37 ) or growth of cell line xenografts ( 37 , 38 ).…”

Targeting key proteins involved in transcriptional regulation for cancer therapy: Current strategies and future prospective

“…[201][202][203] To overcome these insufficiencies and explore novel BCL6 inhibitors with potent bioactivities, an initial screening of in-house libraries containing the diaminopyrimidine scaffold and other skeletons was implemented by our laboratory in consideration of the fact that the majority of known BCL6 inhibitors possess the homologous diaminopyrimidine scaffold. 204 A compound with a diaminopyrimidine scaffold was identified as the hit that blocked the interaction between BCL6 BTB and the corepressor SMRT in a micromolar range. Then a series of novel N-phenyl-4-pyrimidinamine derivatives as BCL6 inhibitors were discovered based on the initial hit, and the lead compound 14j were identified via the subsequent structure−activity relationship studies (Figure 5).…”

Synthesis, insecticidal activities and DFT study of pyrimidin-4-amine derivatives containing the 1,2,4-oxadiazole motif

“…Pyrimidine is a classic nitrogen-containing heterocycle in natural products, such as caffeine, uracil, variolin B, thymine, cytosine, vitamin B1, theophylline, and heteromine. More importantly, reported synthetic pyrimidine compounds have diverse activities, such as fungicidal [1], antitumor [2], antioxidant [3], insecticidal [4], acaricidal [5], and anti-HIV activities [6]. Some of them have been developed as commercial pesticides or pharmaceuticals, especially for pyridineamine derivatives.…”