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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.

Background: The transcription factor B cell lymphoma 6 (BCL6) is an oncogenic driver of diffuse large B cell lymphoma (DLBCL) and mediates lymphomagenesis through transcriptional repression of its target genes by recruiting corepressors to its N-terminal broad-complex/tramtrack/bric-a-brac (BTB) domain. Blocking the protein-protein interactions of BCL6 and its corepressors has been proposed as an effective approach for the treatment of DLBCL. However, BCL6 inhibitors with excellent drug-like properties are rare. Hence, the development of BCL6 inhibitors is worth pursuing.Methods: We screened our internal chemical library by luciferase reporter assay and Homogenous Time Resolved Fluorescence (HTRF) assay and a small molecule compound named WK500B was identi ed.The binding a nity between WK500B and BCL6 was evaluated by surface plasmon resonance (SPR) assay and the binding mode of WK500B and BCL6 was predicted by molecular docking. The function evaluation and anti-cancer activity of WK500B in vitro and in vivo was detected by immuno uorescence assay, Real-Time Quantitative PCR, cell proliferation assay, cell cycle assay, cell apoptosis assay, enzymelinked immunosorbent assay (ELISA), germinal centre (GC) formation mouse model and mouse xenograft model.Results: WK500B engaged BCL6 inside cells, blocked BCL6 repression complexes, reactivated BCL6 target genes, killed DLBCL cells and caused apoptosis as well as cell cycle arrest. In animal models, WK500B inhibited germinal centre formation and DLBCL tumor growth without toxic and side effects.Moreover, WK500B showed favourable pharmacokinetics and presented superior druggability compared to other BCL6 inhibitors.Conclusions: WK500B showed strong e cacy and favourable pharmacokinetics and presented superior druggability compared to other BCL6 inhibitors. So, WK500B is a promising candidate that could be developed as an effective orally available therapeutic agent for DLBCL.

Introduction Dragendorff's reagent has low sensitivity and non‐specificity for some alkaloids. A new alkaloid derivatisation reagent has been developed and optimised by using a Box–Behnken design method. This new reagent is applicable for structurally diverse natural alkaloids, and is proposed as a universal alkaloid staining reagent. Objective To establish an efficient and sensitive thin‐layer chromatography (TLC) identification method for Leonuri Herba and Leonuri Fructus to characterise their differences and similarities. Method Three key components (bismuth subnitrate, potassium iodide and iodine) in the derivatisation reaction were re‐constructed and optimised using a response surface method. Different inorganic acids, essential additives of the staining reaction, were compared by a single‐factor experiment design. Results This newly optimised reagent for alkaloids reported in this study, named the enhanced Dragendorff–Wagner's reagent, is composed of 0.82% bismuth subnitrate, 11.1% potassium iodide and 0.76% iodine in 38% phosphoric acid solution. Validation results indicate that the TLC spot of stachydrine stained with the enhanced Dragendorff–Wagner's reagent had a limit of detection of 2.0 μg, good intra‐ and inter‐plate, and intra‐ and intra‐day precisions with relative standard devition values less than 5.0%, and stability over 90 min. Conclusion This enhanced Dragendorff–Wagner's reagent was applied for TLC identification of 16 reference alkaloids representing 11 structural skeletons, and two closely related herbs (Leonuri Herba and Leonuri Fructus). This newly enhanced Dragendorff–Wagner's reagent is a universal, effective, and sensitive staining reagent for alkaloids.

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