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

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

  • Clin Cancer Res. 2019 Dec 15;25(24):7527-7539. doi: 10.1158/1078-0432.CCR-19-0516.
Linyu Yang  # 1 Qiang Qiu  # 1 Minghai Tang  # 1 Fang Wang 1 Yuyao Yi 2 Dongni Yi 2 Zhuang Yang 1 Zejiang Zhu 1 Shoujun Zheng 1 Jianhong Yang 1 Heying Pei 1 Li Zheng 1 Yong Chen 1 Liping Gou 1 Liya Luo 1 Xing Deng 1 Haoyu Ye 1 Yiguo Hu 3 Ting Niu 3 2 Lijuan Chen 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, China.
  • 2 Department of Hematology and Research Laboratory of Hematology, West China Hospital of Sichuan University, Chengdu, China.
  • 3 State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, China. chenlijuan125@163.com tingniu@sina.com huyiguo@scu.edu.cn.
  • # Contributed equally.
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+ 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.

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