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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 identified. The binding affinity 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 immunofluorescence assay, Real-Time Quantitative PCR, cell proliferation assay, cell cycle assay, cell apoptosis assay, enzyme-linked 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 efficacy 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.

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 N4-(3-chloro-4-methoxyphenyl)-N2-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.

Pancreatic cancer is one of the most common cancers with an extremely low survival rate. Metastasis, as one of the key reasons of cancer-related death, is found in more than 50% pancreatic cancer patients at diagnosis. Novel therapeutic targets and drugs blocking cancer metastasis are urgently needed. Herein, we report a series of 1,5-diaryl-1,2,4-triazole derivatives as potent antimetastatic agents. Lead compound 6y displayed effective antimetastatic activities in pancreatic cancer in vitro and in vivo. Concomitant studies indicated that 6y probably binds with myoferlin (MYOF), a novel potential antitumor metastasis target, which regulates vesicle trafficking and metastasis-related proteins. Subsequent biophysical and biochemical methods verified that 6y bound to MYOF. Mechanism studies revealed that 6y inhibited pancreatic cancer metastasis through reversing the epithelial mesenchymal transition, inhibiting the secretions of matrix metalloproteinase and blocking the receptor tyrosine kinases. Our findings suggest that targeting MYOF with 6y may be a promising therapeutic strategy to prevent pancreatic cancer metastasis.

Rapid metabolism differentiates cancer cells from normal cells and relies on anaplerotic pathways. However, the mechanisms of anaplerosis‐associated enzymes are rarely understood. The lack of potent and selective antimetabolism drugs restrains further clinical investigations. A small molecule ZY‐444 ((N 4‐((5‐(4‐(benzyloxy)phenyl)‐2‐thiophenyl)methyl)‐N 2‐isobutyl‐2,4‐pyrimidinediamine) is discovered to inhibit cancer cell proliferation specifically, having potent efficacies against tumor growth, metastasis, and recurrence. ZY‐444 binds to cellular pyruvate carboxylase (PC), a key anaplerotic enzyme of the tricarboxylic acid cycle, and inactivates its catalytic activity. PC inhibition suppresses breast cancer growth and metastasis through inhibiting the Wnt/β‐catenin/Snail signaling pathway. Lower PC expression in patient tumors is correlated with significant survival benefits. Comparative profiles of PC expression in cancer versus normal tissues implicate the tumor selectivity of ZY‐444. Overall, ZY‐444 holds promise therapeutically as an anti‐cancer metabolism agent., A specific metabolic inhibitor (named ZY‐444) of pyruvate carboxylase (PC), the key anaplerosis enzyme, is discovered to exhibit cancer selectivity as well as great therapeutic efficacy against breast cancer progression. This study also demonstrates the mechanistic roles of PC in breast cancer progression and identifies the crosstalk between the canonical Wnt pathway and cancer anaplerosis.

As the continuous rise in the incidence of antibiotic resistance, it is urgent to develop novel chemical scaffolds with antibacterial activities to control the spread of resistance to conventional antibiotics. In this study, a series of phenylthiazole and phenylthiophene pyrimidindiamine derivatives were designed and synthesized by modifying the hit compound (N2-isobutyl-N4-((4-methyl-2-phenylthiazol-5-yl)methyl) pyrimidine-2,4-diamine) and their antibacterial activities were evaluated both in vitro and in vivo. Among the tested compounds, compound 14g (N4-((5-(3-bromophenyl)thiophen-2-yl)methyl)-N2-isobutylpyrimidine-2,4-diamine) displayed the best antibacterial activities, which was not only capable of inhibiting E. coli and S. aureus growth at concentrations as low as 2 and 3 μg/mL in vitro, but also efficacious in a mice model of bacteremia in vivo. Unlike conventional antibiotics, compound 14g was elucidated to mainly destroy the bacterial cell membrane, with the dissipation of membrane potential and leakage of contents, ultimately leading to cell death. The destruction of cell structure is challenging to induce bacterial resistance, which suggested that compound 14g may be a kind of promising alternatives to antibiotics against bacteria.

Therapeutics of metastatic or triple-negative breast cancer are still challenging in clinical. Herein we demonstrated the design and optimization of a series of hybrid of 2,4-diaminopyrimidine and arylthiazole derivatives for their anti-proliferative properties against two breast cancer cell lines (MCF-7 as human breast cancer and MDA-MB-231 as triple-negative breast cancer). More importantly, some of those compounds with potent antiproliferative activities also indicated excellent inhibitory activities against MDA-MB-231 cell migration. These results suggested that the new series of hybridation of aryl-thiazoles and aminopyrimidines could be identified and developed as novel highly potential anticancer agents against the triple-negative breast cancer as well as metastatic one in the future.

Several 6-substituted tetrahydrocarbazole derivatives were designed, synthesized and evaluated for the antibacterial activities against Staphylococcus aureus Newman strain. Subsequently, 2,4-diaminopyrimidine scaffold was merged with the tetrahydrocarbazole unit to generate a series of novel hybrid derivatives and the antibacterial activities were also investigated. Among these novel hybrids, compound 12c showed the most potent activity with a MIC of 0.39–0.78 μg/mL against S. aureus Newman and Escherichia coli AB1157 strain. In addition, compound 12c exhibited low MIC values against a panel of multidrug-resistant strains of S. aureus.

Microwave absorbing properties of the composites containing inductive activated carbon-fiber felt screens (IACFFSs) and vertical-arranged carbon fibers (VACFs) have been investigated, respectively. It is found that the reflection properties of the composites containing IACFFSs are greatly affected by the element configurations of IACFFSs. With the interval between strips and the width of the strips in the IACFFS decreased, the absorbing properties of the composites are improved. The composite obtains a reflection loss below −10 dB in 8–18 GHz, which covers the frequency region of the radar, when the interval between strips and the width of the strips are 7 mm and 5 mm, respectively. The space between the adjacent carbon fibers is critical for the absorbing characteristics of the composites containing VACFs. The composite achieves a reflection loss below −10 dB over 7.6 GHz when the space is 4 mm. By applying the block design method, the composite was divided into four sub-regions, which were centrosymmetrical and included two IACFFSs and two VACF regions. The composite achieves a reflection loss below −20 dB in 11.8–18 GHz and the minimum value reaches −30 dB when the interval between strips, the width of the strips and the fiber space are 10 mm, 5 mm and 8 mm, respectively.