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Inhibiting a specific target in cancer cells and reducing unwanted side effects has become a promising strategy in pancreatic cancer treatment. MAP4K4 is associated with pancreatic cancer development and correlates with poor clinical outcomes. By phosphorylating MKK4, proteins associated with cell apoptosis and survival are translated. Therefore, inhibiting MAP4K4 activity in pancreatic tumours is a new therapeutic strategy. Herein, we performed a structure-based virtual screening to identify MAP4K4 inhibitors and discovered the compound F389-0746 with a potent inhibition (IC50 120.7 nM). The results of kinase profiling revealed that F389-0746 was highly selective to MAP4K4 and less likely to cause side effects. Results of in vitro experiments showed that F389-0746 significantly suppressed cancer cell growth and viability. Results of in vivo experiments showed that F389-0746 displayed comparable tumour growth inhibition with the group treated with gemcitabine. These findings suggest that F389-0746 has promising potential to be further developed as a novel pancreatic cancer treatment. We identified a novel MAP4K4 inhibitor using a structure-based virtual screening strategy. Kinase profiling showed high selectivity towards MAP4K4. The identified inhibitor suppressed pancreatic cancer cell growth and viability in vitro. The inhibitor downregulated the MKK4-JNK signalling pathway. The inhibitor suppressed tumour growth in vivo. [ABSTRACT FROM AUTHOR]

Five pathways involving different ring structures led to generation of fourteen thienylbenzamides (7–20) which display the structure-activity relationships of class I HDAC inhibitors. All the synthesised compounds inhibit HDAC1 and HDAC2 selectively over other isoforms and many inhibit DLD1 and HCT116 cells more effectively than a parent compound. Compounds 8 and 16 inhibit HCT116 cells by activation of the apoptosis pathway. [ABSTRACT FROM AUTHOR]

A series of 3-subsituted quinolinehydroxamic acids has been synthesised and evaluated for their effect on human lung cancer cell line (A549), human colorectal cancer cell line (HCT116) and HDAC isoforms 1, 2, 6, and 8. The results indicated that substitution at C3 of quinoline is favoured for HDAC6 selectivity. Two compounds (25 and 26) were also found to be potent anti-proliferative compounds with IC50 values ranging from 1.29 to 2.13 µM against A549 and HCT116 cells. These compounds displayed remarkable selectivity for HDAC6 over other HDAC isoforms with nanomolar IC50 values. Western blot analysis revealed that compounds of this series activate apoptotic caspase pathway as indicated by cleavage of caspase 3, 8, and 9 and also increase phosphorylated H2AX thus inducing DNA double strand fragmentation in a concentration dependent manner. Flow cytometric analysis also displayed a dose dependent increase of cell population in sub G1 phase. [ABSTRACT FROM AUTHOR]

Vascular dementia (VaD) is the second most common cause of dementia, but the treatment is still lacking. Although many studies have reported that histone deacetylase inhibitors (HDACis) confer protective effects against ischemic and hypoxic injuries, their role in VaD is still uncertain. Previous studies shown, one HDACi protected against cognitive decline in animals with chronic cerebral hypoperfusion (CCH). However, the underlying mechanisms remain elusive. In this study, we tested several 10,11‐dihydro‐5H‐dibenzo[b,f]azepine hydroxamates, which act as HDACis in the CCH model (in vivo), and SH‐SY5Y (neuroblastoma cells) with oxygen‐glucose deprivation (OGD, in vitro). We identified a compound 13, which exhibited the best cell viability under OGD. The compound 13 could increase, in part, the protein levels of brain‐derived neurotrophic factor (BDNF). It increased acetylation status on lysine 14 residue of histone 3 (H3K14) and lysine 5 of histone 4 (H4K5). We further clarified which promoters (I, II, III, IV or IX) could be affected by histone acetylation altered by compound 13. The results of chromatin immunoprecipitation and Q‐PCR analysis indicate that an increase in H3K14 acetylation leads to an increase in the expression of BDNF promoter II, while an increase in H4K5 acetylation results in an increase in the activity of BDNF promoter II and III. Afterwards, these cause an increase in the expression of BDNF exon II, III and coding exon IX. In summary, the HDACi compound 13 may increase BDNF specific isoforms expression to rescue the ischemic and hypoxic injuries through changes of acetylation on histones. [ABSTRACT FROM AUTHOR]

Ribonucleotide reductase (RR) catalyses the rate-limiting step of dNTP synthesis, establishing it as an important cancer target. While RR is traditionally inhibited by nucleoside-based antimetabolites, we recently discovered a naphthyl salicyl acyl hydrazone-based inhibitor (NSAH) that binds reversibly to the catalytic site (C-site). Here we report the synthesis and in vitro evaluation of 13 distinct compounds (TP1-13) with improved binding to hRR over NSAH (TP8), with lower KD's and more predicted residue interactions. Moreover, TP6 displayed the greatest growth inhibiting effect in the Panc1 pancreatic cancer cell line with an IC50 of 0.393 µM. This represents more than a 2-fold improvement over NSAH, making TP6 the most potent compound against pancreatic cancer emerging from the hydrazone inhibitors. NSAH was optimised by the addition of cyclic and polar groups replacing the naphthyl moiety, which occupies the phosphate-binding pocket in the C-site, establishing a new direction in inhibitor design. [ABSTRACT FROM AUTHOR]

The combination cancer therapy is a new strategy to circumvent drug resistance for the treatment of high metastasis and advanced malignancies. Herein, we developed a synthesized compound MPT0B451 that display inhibitory effect against histone deacetylase (HDAC) 6 and tubulin assembly. Our data demonstrated that MPT0B451 significantly inhibited cancer cell growths in HL-60 and PC-3 cells due to inhibition of HDAC activity. MPT0B451 also markedly increased caspase-mediated apoptosis in these cells. The cell cycle analysis showed mitotic arrest induced by MPT0B451 with enhanced expression of G2/M transition proteins. Moreover, molecular docking analysis supported MPT0B451 as a dual HDAC6 and tubulin inhibitor. Finally, MPT0B451 led to tumor growth inhibition (TGI) in HL-60 and PC-3 xenograft models. These findings indicated that MPT0B451 has dual inhibition effects for HDAC6 and tubulin, and also contributed to G2/M arrest followed by apoptotic induction. Together, our results suggested that MPT0B451 may serve as a potent anti-cancer treatment regimen in human prostate cancer and acute myeloid leukemia. [ABSTRACT FROM AUTHOR]

Interleukin-1β (IL-1β) upregulates intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expressions in osteoarthritis fibroblast-like synoviocytes (OA-FLS) via nuclear factor (NF)-κB-mediated mechanism; enhancement of leukocyte infiltration and upregulation of proinflammatory mediators play a crucial role in OA pathophysiology. MicroRNA (miR)-146a suppresses inflammatory responses by inhibiting NF-κB activity and target gene expression, and epigenetic mechanisms are reportedly involved in miR expression regulation. Here, we aimed to verify the inhibition of ICAM-1/VCAM-1 expression in OA-FLS on denbinobin treatment and to determine whether this inhibition was due to the miR-146a-dependent pathway. We also assessed the epigenetic regulation caused by histone acetyltransferases involved in denbinobin action. Denbinobin attenuated the upregulation of IL-1β-induced ICAM-1/VCAM-1 expression and monocyte adhesion to OA-FLS. The mechanism underlying the inhibitory effects of denbinobin involved miR-146a induction, which in turn inhibited NF-κB signaling. This is because miR-146a inhibitor abrogated the inhibitory effects of denbinobin. Furthermore, histone acetyltransferase inhibitor attenuated the denbinobin-induced upregulation of miR-146a expression and inhibited the acetylation of NF-κB-binding sites located within the miR-146a promoter region. These data suggest that an epigenetic mechanism plays a crucial role in the upregulation of miR-146a expression in response to denbinobin treatment. Our overall findings suggest that denbinobin can be used as a potent anti-inflammatory agent. Key message: • Denbinobin inhibited IL-1β-induced ICAM-1/VCAM-1 expression and monocyte adhesion to OA-FLS. • It was due to denbinobin increased miR-146a level, which in turn inhibited NF-κB signaling. • Our overall findings suggest that denbinobin can be used as a potent anti-inflammatory agent. [ABSTRACT FROM AUTHOR]