Novel oral histone deacetylase inhibitor, MPT0E028, displays potent growth-inhibitory activity against human B-cell lymphomain vitroandin vivo

Abstract

Histone deacetylase (HDAC) inhibitor has been a promising therapeutic option in cancer therapy due to its ability to induce growth arrest, differentiation, and apoptosis. In this study, we demonstrated that MPT0E028, a novel HDAC inhibitor, reduces the viability of B-cell lymphomas by inducing apoptosis and shows a more potent HDAC inhibitory effect compared to SAHA, the first HDAC inhibitor approved by the FDA. In addition to HDACs inhibition, MPT0E028 also possesses potent direct Akt targeting ability as measured by the kinome diversity screening assay. Also, MPT0E028 reduces Akt phosphorylation in B-cell lymphoma with an IC50 value lower than SAHA. Transient transfection assay revealed that both targeting HDACs and Akt contribute to the apoptosis induced by MPT0E028, with both mechanisms functioning independently. Microarray analysis also shows that MPT0E028 may regulate many oncogenes expression (e.g., TP53, MYC, STAT family). Furthermore, in vivo animal model experiments demonstrated that MPT0E028 (50–200 mg/kg, po, qd) prolongs the survival rate of mice bearing human B-cell lymphoma Ramos cells and inhibits tumor growth in BJAB xenograft model. In summary, MPT0E028 possesses strong in vitro and in vivo activity against malignant cells, representing a potential therapeutic approach for cancer therapy.

CN133, a Novel Brain-Penetrating Histone Deacetylase Inhibitor, Hampers Tumor Growth in Patient-Derived Pediatric Posterior Fossa Ependymoma Models

“…CN133 also negatively impacts on the PI3K/AKT/mTOR pathway, as evidenced by the reduction in phosphorylated levels of AKT S473 and the downstream target ribosomal protein S6. Similar results have been observed in B-lymphoma cells treated with the HDACi MPT0E028 [ 30 ].…”

M344 promotes nonamyloidogenic amyloid precursor protein processing while normalizing Alzheimer’s disease genes and improving memory

“…We therefore suggest that drug efficacy relates to C max (discussed above) and that prolonged daily exposure is likely not required. The observations that ( i ) in vivo efficacy was observed with much lower doses of this HDACi than typically used in mouse models of cancer and other CNS disorders ( 81 , 82 ) and that ( ii ) short periods of high brain exposure seem to be sufficient for efficacy indicate that it may be possible to avoid adverse effects in possible future attempts to use M344 (or related compounds) to treat humans with AD or related disorders.…”

HDAC inhibitors overcome immunotherapy resistance in B-cell lymphoma

“…Seven HDAC inhibitors, including CI-994, panobinostat, SBHA, vorinostat, scriptaid, trichostatin A and tubacin, exhibit dose-dependent inhibitory effects on proliferation of a canine B-cell lymphoma line (Dias et al, 2018). Another pan-HDAC inhibitor, MPT0E028, shows a potent HDAC inhibitory effect, that leads to increased apoptosis, and prolongs the overall survival of recipient mice bearing human B-cell lymphoma in a xenograft model (Huang et al, 2015). Our studies also demonstrate cytotoxic effects of HDAC inhibitors on B-cell lymphomas (Wang et al, 2019).…”