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