pracinostat (SB939)

We identified that histone deacetylases (HDACs) were prominent candidates, and subsequently identified that the HDAC inhibitors mocetinostat and pracinostat, as well as the combined HDAC-epidermal growth factor receptor inhibitor CUDC-101, were effective at radiosensitising cell models of HNSCC (FaDu, A253, UMSCC11b) through their impact on both spheroid growth and clonogenic survival assays. We also demonstrated that this combinatorial strategy leads to inhibition of the repair of DNA double-strand breaks through the neutral comet assay and γH2AX foci analysis using immunofluorescence microscopy, providing a mechanism of action through which HDAC inhibition functions in HNSCC radiosensitisation. We believe that this approach should be further investigated in preclinical models, in order to realise the full therapeutic potential of HDAC inhibition for the radiosensitisation of HNSCC, eventually leading to improved patient treatment efficacy and outcomes.

The relationship between DLBCL and glutathione-related genes was uncovered by our research, and six glutathione genes were linked to DLBCL. These genes might be used as diagnostic biomarkers or targets for treatment for DLBCL patients.

Overall, our results suggest that IDO1 tryptophan metabolites produced by neuronal cells may act on AHR in pathogenic CD4+ T cells in a paracrine fashion in the CNS and that the specific induction of IDO1 expression in neurons at disease-afflicted sites can be considered a therapeutic approach to block the progression of multiple sclerosis without affecting systemic immunity.

A series of novel benzimidazole derivatives were designed and synthesised based on the structures of reported oral available ALK inhibitor and HDAC inhibitor, pracinostat...Compound 3b also inhibited various ALK mutants known to be involved in crizotinib resistance, including mutant L1196M (IC50, 4.9 nM)...At 20 mg/kg, 3b inhibited tumour growth by 85% yet had a negligible effect on mean body weight. These results suggest a attracting route for the further research and optimisation of dual ALK/HDAC inhibitors.

Knockdown of ALDH1A3 prevented HGSOC tumorigenesis and enhanced cell sensitivity to paclitaxel or cisplatin...Treatment of exogenous acetate with NaOAc or inhibition of histone deacetylase with Pracinostat increased H3K27ac and PITX1 levels. CHIP assay demonstrated a significant enrichment of H3K27ac at the PITX1 promoter, and ALDH1A3 knockdown reduced the binding between H3K27ac and PITX1. Taken together, our data suggest that ALDH1A3, transcriptional activated by HIF-1α, promotes tumorigenesis and decreases chemosensitivity by increasing H3K27ac of PITX1 promoter in HGSOC.

AT.9283, EXEL.2280, Gilteritinib, and Pracinostat had the largest correlation (absolute value) with a risk score. Four risk model genes (mRNAs), 12 miRNAs, and 21 lncRNAs formed an mRNA-miRNA-lncRNA network, containing HOXA10-hsa-miR-129-5p-LINC00689 and KIF18A-hsa-miR-221-3p-DANCR. Through bioinformatics, we constructed a prognostic model of m6A-associated anoikis genes in LGG, providing new ideas for research related to the prognosis and treatment of LGG.

The ability of SB939 to sensitize HT-29 cells suggests that SB939 can induce essential changes in cell signaling pathways. Thus, the pan-HDAC inhibitor SB939 sensitizes TRAIL-induced apoptosis via up-regulation of DR5, and SB939-TRAIL combined treatment may target the MAPK pathways and serve as an effective therapeutic strategy against CRC.

These included clinical ALL drugs dexamethasone and daunorubicin, proteasome inhibitor carfilzomib, BCL2/BCLxL inhibitor navitoclax, and histone deacetylase inhibitors romidepsin and pracinostat...Combination of idasanutlin with navitoclax exhibited both the greatest and most consistent synergistic interaction (δ = 24.7±8.7, n=11) of the candidate combinations (n=10) across an extensive landscape of dose combinations; additionally alluding to synergy indiscriminate of ALL subtype...Together, we provide strong evidence that concurrent targeting of MDM2-p53 binding and BCL2/BCLxL leads to potent and synergistic enhancement of apoptotic cell death in a range of high-risk ALL subtypes. The proposed combination of two clinical-stage compounds could have considerable positive clinical impact for the treatment of adult ALL.

Our results strongly support the potential clinical use of pracinostat as a novel therapy for human glioma in the near future.

P1, N=14, Completed, Medical College of Wisconsin | Active, not recruiting --> Completed

On the contrary, high mRNA expressions of CBL, FYN, LRKK2, and SOCS2 were associated with a significantly better prognosis. Furthermore, our drug target analysis for these hub genes suggests a potential use of Trichostatin A, Pracinostat, TGX-221, PHA-793887, AG-879, and IMD0354 antineoplastic agents to reverse the expression of these DEGs in NSCLC patients.

CDH1 breast and gastric cells were more sensitive to the pan-HDAC inhibitors entinostat, pracinostat, mocetinostat and vorinostat than wild-type cells, with an elevated growth inhibition that was, in part, attributable to increased apoptosis. Finally, entinostat enhanced Cdh1 expression in heterozygous Cdh1 murine organoids. In conclusion, entinostat is a promising drug for the chemoprevention and/or treatment of HDGC and may also be beneficial for the treatment of sporadic CDH1-deficient cancers.

Background: Adaptive resistance mechanisms leading to treatment failure have been identified in older patients receiving venetoclax (VEN) in combination with either azacitidine or low dose cytarabine (LDAC) as frontline therapy for acute myeloid leukemia (AML)...To mitigate VEN resistance associated with activated kinases in NON-ADV risk AML, midostaurin (MIDO), a FLT3/multi-kinase inhibitor, was incorporated in combination with VEN. To address VEN resistance associated with TP53 defects in ADV risk AML, a HDAC inhibitor pracinostat (PRAN) was incorporated in accordance with pre-clinical studies suggesting synergistic induction of TP53 independent cell death with VEN plus HDAC inhibition (Salmon et al , ASH 2018)... The addition of MIDO or PRAN to VEN-LDAC was tolerable in older/unfit patients with treatment naïve AML. Preliminary efficacy with this risk-stratified approach compared favorably to prior studies with VEN-LDAC alone (Wei et al Blood 2020: CR+CRi 56% in NON-ADV, 28% in ADV). The randomized phase 2 part of this tandem triplet strategy with the goal of preventing adaptive resistance is underway.

Moreover, treatment of AML cells with the HDAC inhibitor, pracinostat, and LSD1 inhibitor, GSK2879552, resulted in growth inhibition both in vitro and in vivo. High BCL11A expression is associated with worse prognosis in human AML patients. Blocking of BCL11A expression upregulates the expression of PU.1 target genes, and inhibits the growth of HL-60 cells and their engraftment to the bone marrow, suggesting that BCL11A is involved in human myeloid malignancies via the suppression of PU.1 transcriptional activity.

P1, N=14, Active, not recruiting, Medical College of Wisconsin | Recruiting --> Active, not recruiting

P1, N=18, Recruiting, Medical College of Wisconsin | Trial completion date: Mar 2022 --> Mar 2023 | Trial primary completion date: May 2021 --> May 2022

P1, N=18, Recruiting, Medical College of Wisconsin | Trial completion date: Mar 2021 --> Mar 2022 | Trial primary completion date: May 2020 --> May 2021

Our findings indicate that SB939 may be an effective therapeutic option for treating advanced breast cancer.

Novel treatment regimens are required for castration-resistant prostate cancers (CRPCs) that become unresponsive to standard treatments, such as docetaxel and enzalutamide...Four HDAC inhibitors, vorinostat, pracinostat, panobinostat and romidepsin, underwent phase II clinical trials for prostate cancers; however, phase III trials were not recommended due to a majority of patients exhibiting either toxicity or disease progression...The review focuses on three themes: evolution of androgen receptor-negative prostate cancers, development of resistance mechanisms and differential effects of HDACs. In conclusion, advancements can be made in this field by characterizing HDACs in prostate tumors more extensively, as this will allow more specific drugs catering to the specific HDAC subtypes to be designed.