nexturastat A

Our results demonstrate the critical regulatory role of HDAC6 in phagocytosis and innate immunity for the first time, further underscoring the use of these inhibitors to potentiate CD47 immune checkpoint blockade therapeutic strategies.

A series of hybrid inhibitors, combining pharmacophores of known kinase inhibitors bearing anilino-purines (ruxolitinib, ibrutinib) and benzohydroxamate HDAC inhibitors (nexturastat A), were generated in the present study. The kinase inhibition profile of compounds 4d-f allows selective cytotoxicity, with minimal effects on non-tumorigenic cells. Moreover, these compounds have favorable pharmacokinetic profiles, with high stability in human liver microsomes (e.g., see t: >120 min for 4f), low intrinsic clearance, and lack of significant inhibition of four major CYP450 isoforms.

We investigated whether HDAC6 inhibitors (HDAC6is), such as Nexturastat A (NextA), affected STAT3 activation in CRC cells. First, we found that NextA is less cytotoxic than the non-selective HDACis panobinostat...These results suggest that treatments with NextA reduce the functionality of STAT3 in CRC cells, impacting the expression of immunomodulatory genes involved in the inflammatory and immune responses. Therefore, targeting HDAC6 may represent an interesting adjuvant strategy in combination with immunotherapy.

NexturastatA antitumor activity was assayed in both WT and HR cells and was effective in reducing cell viability. Furthermore, HDAC6 activity was 15% to 40 % lower in HR subclones as compared to the WT. We finally exposed cells to a combination of low NextA concentrations and Trastuzumab, observing a synergistic effect of the drugs and a reversal of drug resistance in BT474HR subclone.ConclusionOur findings encourage the exploration of the mechanism underlying the effects of HDAC6 inhibition and HER-2 signaling blockade combination.

Bone marrow-derived macrophages (BMDMs) isolated from C57BL/6 mice were pre-treated with HDAC6 (NexturastatA) or HDAC11 (FT895) inhibitors prior to polarizing them to M1 and M2 phenotypes...Transcriptomics and single-cell secretome analyses of macrophages indicate that HDAC6 and HDAC11 affects macrophage function in diametrically opposite directions. Therefore, our study underscores the importance of class-selective inhibition of HDACs over pan-HDAC inhibitors and the potential use of selective HDAC inhibitors as a therapeutic option to control macrophage phenotype in cancer and other conditions.

We also demonstrated that the combination of systemic administration of the HDAC6 inhibitor Nexturastat A and intertumoral delivery of anti-CD47 reduced SM1 melanoma growth in vivo by increasing immune cell infiltration in the tumor microenvironment. Collectively our results suggest that HDAC6 inhibitors synergize with CD47 blockade to reduce tumor growth and enhance innate antitumor immunity.

Although the cell surface expression of CD26 was relatively low or not detected on 5 MM cell lines (KMS26, KMS27, KMS28, KMS11, RPMI8226), the increased expression in CD26 levels was detectable within 24 h of the treatment with HDAC1i; FK228, HDAC3i; BG45, MS-275, RG2833 or HDAC6i; nexturastat A, tubastatin A, ACY-1215 as well as broad HDACi; LBH-589, SAHA... Combination with isoform-selective HDACi not only shows anti-MM activity but supports as immunopotentiators by sensitizing CD26neg MM cells to CD26mAb and augment its cytotoxicity against MM cells.

Here, we investigate whether HDAC6 affects STAT3 activation in CRC cells, through treatments with Nexturastat A (NextA), a specific HDAC6 inhibitor, that indirectly, decreases the levels of activating post-translational modifications on STAT3 analyzed by Western blot and flow cytometry...These results suggest that treatments with specific HDAC6 inhibitors would reduce the functionality of STAT3 in CRC cells, impacting the expression of immunomodulator genes involved in the immune response, as IL-10, PD-L1 and others. Therefore, the use of specific HDAC6 inhibitors may be a reasonable and an interesting adjuvant strategy for help in checkpoint inhibitors immunotherapy, since HDAC6 inhibitors would indirectly decrease PD-L1 expression, one of the checkpoint inhibitors of immune system.

Several compounds of these structural classes have been approved for clinical uses to treat different types of cancer, such as givinostat (ITF2357) and belinostat (PXD-101)...Two new series of N-hydroxybenzamides and N-hydroxypropenamides analogues (4a-j, 6a-j) designed based on the structural features of nexturastat A, AR-42, and PXD-101, were synthesized and evaluated for HDAC inhibitory potency as well as cytotoxicity against three human cancer cell lines (SW620 (colorectal adenocarcinoma), PC3 (prostate adenocarcinoma), and NCI-H23 (adenocarcinoma, non-small cell lung cancer)...Various compounds, e.g. 6a-e, especially compound 6e, were up to 5-fold more potent than suberanilohydroxamic acid (SAHA) in terms of cytotoxicity...These compounds also comparably inhibited HDACs with IC50 values in sub-micromolar range. Docking experiments showed that these compounds bound to HDAC2 at the enzyme active binding site with the same binding mode of SAHA, but with higher binding affinities.