Purinostat Mesylate is a uniquely potent and selective inhibitor of HDACs for the treatment of BCR-ABL-induced B-cell acute lymphoblastic leukemia
2019
Purpose: This study was to perform preclinical evaluation of a novel class I and IIb HDAC selective inhibitor, Purinostat Mesylate (PM), for the treatment of Ph+ B-ALL. Experimental Design: Biochemical assays were used to test enzymatic activity inhibition of PM. Ph+ leukemic cell lines and patient cells were used to evaluate PM 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 PM for refractory or relapsed Ph+ B-ALL. Long-term toxicity and hERG blockade assays were used to safety evaluation of PM. Results: PM, a class I and IIb HDAC highly selective inhibitor, exhibited robust antitumor activity in hematological cancers. PM at low nanomolar concentration induced apoptosis, and down-regulated BCR-ABL and c-MYC expression in Ph+ leukemia cell lines and primary Ph+ B-ALL cells from relapsed patients. PM 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 relapsed Ph+ B-ALL patients post TKI treatment. In addition, PM possesses favorable pharmacokinetics and low toxicity properties. Conclusions: PM provides a new therapeutic strategy for Ph+ B-ALL patients including those who relapse after TKI treatment.
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