Purinostat Mesylate Is a Uniquely Potent and Selective Inhibitor of HDACs for the Treatment of BCR-ABL–Induced B-Cell Acute Lymphoblastic Leukemia

Abstract

Purpose: This study was to perform preclinical evaluation of a novel class I and IIb HDAC-selective inhibitor, purinostat mesylate, for the treatment of Ph þ B-cell acute lymphoblastic leukemia (B-ALL).Experimental Design: Biochemical assays were used to test enzymatic activity inhibition of purinostat mesylate. Ph þ leukemic cell lines and patient cells were used to evaluate purinostat mesylate activity in vitro. BL-2 secondary transplantation Ph þ B-ALL mouse model was used to validate its efficacy, mechanism, and pharmacokinetics properties in vivo. BCR-ABL(T315I)-induced primary B-ALL mouse model and PDX mouse model derived from relapsed Ph þ B-ALL patient post TKI treatment were used to determine the antitumor effect of purinostat mesylate for refractory or relapsed Ph þ B-ALL. Long-term toxicity and hERG blockade assays were used to safety evaluation of purinostat mesylate. Results: Purinostat mesylate, a class I and IIb HDAC highly selective inhibitor, exhibited robust antitumor activity in hematologic cancers. Purinostat mesylate at low nanomolar concentration induced apoptosis, and downregulated BCR-ABL and c-MYC expression in Ph þ leukemia cell lines and primary Ph þ B-ALL cells from relapsed patients. Purinostat mesylate efficiently attenuated Ph þ B-ALL progression and significantly prolonged the survival both in BL-2 secondary transplantation model with clinical patient symptoms of Ph þ B-ALL, BCR-ABL(T315I)-induced primary B-ALL mouse model, and PDX model derived from patients with relapsed Ph þ B-ALL post TKI treatment. In addition, purinostat mesylate possesses favorable pharmacokinetics and low toxicity properties.Conclusions: Purinostat mesylate provides a new therapeutic strategy for patients with Ph þ B-ALL, including those who relapse after TKI treatment.

Assessment of Thiosemicarbazone‐Containing Compounds as Potential Antileukemia Agents against P‐gp Overexpressing Drug Resistant K562/A02 Cells

“…HDACs play significant roles during the leukemogenesis [14–16] . In order to investigate the effect of the active compound 3h on HDACs activity, the fluorescent‐based HDAC biochemical activity were subsequently determined accordingly our previous method [24] .…”

“…More importantly, thiosemicarbazones possessed diverse biological activities (i. e., anticancer, antivirus) and several agents with a thiosemicarbazone moiety have been evaluated in clinical trials against malignancies including leukemia [13] . Keeping these in mind and considering that histone deacetylases (HDACs) play a significant role in leukemogenesis, and HDACs inhibitors were reported as promising agents for the treatment of leukemia, [14–16] we speculated that hybridizing the thiosemicarbazone moiety with the HDACs inhibitor pharmacophore might result in compounds with more effective antileukemia activity against resistant leukemic cells overexpressing P‐gp. Thus, seventeen thiosemicarbazone‐containing compounds ( 3a – 3q , Figure 1) with a similar pharmacophore of HDACs inhibitor vorinostat ( SAHA ) were synthesized, and their antiproliferative activities against P‐gp overexpressing K562/A02 cells, and the preliminary mechanisms were subsequently evaluated in this article.…”

MYC’s Fine Line Between B Cell Development and Malignancy

“…The inhibition of SK2 provokes a drastic reduction in ALL cell proliferation through concomitant repression of MYC target genes [54]. Recently, the use of purinostat mesylate (a first-in-class histone deacetylase (HDAC) inhibitor with reported antitumor activity [55]) has also been shown to downregulate the BCR-ABL1 fusion protein targeting of MYC through the alteration of global histone 3 (H3) and histone 4 (H4) acetylation [56]. These studies reveal chromatin remodeling to be a promising therapeutic strategy in BCR-ABL1 + ALL.…”

“…In this sense, newly developed compounds that selectively inhibit specific HDAC subtypes are gaining relevance in the treatment of hematological malignancies [97]. For instance, class I/IIb-selective HDACi purinostat has demonstrated a direct effect on MYC downregulation [56], while other selective drugs (mocetinostat, entinostat) are already undergoing clinical trials for diverse hematological malignancies [97]. The use of combinatorial therapies merging selective HDACi and classical treatments emerges as a promising therapeutic option, and it is tempting to speculate that its ability to induce apoptosis resides, at least partially, in MYC negative regulation [97].…”

Therapeutic efficacy of an injectable formulation of purinostat mesylate in SU-DHL-6 tumour model

“…Purinostat mesylate (PM), a novel class I and class IIb HDAC inhibitor using the morpholinopurine as the capping group has been reported by our group [ 12 ]. PM has a good inhibitory effect on a variety of B cell-associated haematological tumour cells [ 13 ], but its clinical applications is greatly limited by poor solubility. Cyclodextrin and its derivatives are often used to improve the solubility of hydrophobic drugs [ 14 ].…”