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

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⁺ B-cell acute lymphoblastic leukemia (B-ALL).

Experimental design: Biochemical assays were used to test enzymatic activity inhibition of purinostat mesylate. Ph⁺ leukemic cell lines and patient cells were used to evaluate purinostat mesylate activity in vitro. BL-2 secondary transplantation Ph⁺ 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⁺ B-ALL patient post TKI treatment were used to determine the antitumor effect of purinostat mesylate for refractory or relapsed Ph⁺ 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⁺ leukemia cell lines and primary Ph⁺ B-ALL cells from relapsed patients. Purinostat mesylate efficiently attenuated Ph⁺ B-ALL progression and significantly prolonged the survival both in BL-2 secondary transplantation model with clinical patient symptoms of Ph⁺ B-ALL, Bcr-Abl(T315I)-induced primary B-ALL mouse model, and PDX model derived from patients with relapsed Ph⁺ 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⁺ B-ALL, including those who relapse after TKI treatment.