中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
  4. 新药研究国家重点实验室
Pharmacodynamic, pharmacokinetic, and phase 1a study of bisthianostat, a novel histone deacetylase inhibitor, for the treatment of relapsed or refractory multiple myeloma

文献类型：期刊论文

作者Zhou, Yu-bo4,5; Zhang, Yang-ming1,4,5; Huang, Hong-hui3; Shen, Li-jing3; Han, Xiao-feng3; Hu, Xiao-bei4; Yu, Song-da2,4; Gao, An-hui4; Sheng, Li4; Su, Ming-bo4
刊名ACTA PHARMACOLOGICA SINICA
出版日期2021-08-02
页码9
关键词multiple myeloma HDAC inhibitor bisthianostat pharmacodynamics pharmacokinetics phase 1a clinical trial antitumor drug
ISSN号1671-4083
DOI10.1038/s41401-021-00728-y
通讯作者Nan, Fa-jun(fjnan@simm.ac.cn) ; Li, Jia(jli@simm.ac.cn) ; Hou, Jian(houjian@medmail.com.cn)
英文摘要HDAC inhibitors (HDACis) have been intensively studied for their roles and potential as drug targets in T-cell lymphomas and other hematologic malignancies. Bisthianostat is a novel bisthiazole-based pan-HDACi evolved from natural HDACi largazole. Here, we report the preclinical study of bisthianostat alone and in combination with bortezomib in the treatment of multiple myeloma (MM), as well as preliminary first-in-human findings from an ongoing phase 1a study. Bisthianostat dose dependently induced acetylation of tubulin and H3 and increased PARP cleavage and apoptosis in RPMI-8226 cells. In RPMI-8226 and MM.1S cell xenograft mouse models, oral administration of bisthianostat (50, 75, 100 mg center dot kg(-1)center dot d(-1), bid) for 18 days dose dependently inhibited tumor growth. Furthermore, bisthianostat in combination with bortezomib displayed synergistic antitumor effect against RPMI-8226 and MM.1S cell in vitro and in vivo. Preclinical pharmacokinetic study showed bisthianostat was quickly absorbed with moderate oral bioavailability (F% = 16.9%-35.5%). Bisthianostat tended to distribute in blood with V-ss value of 0.31 L/kg. This distribution parameter might be beneficial to treat hematologic neoplasms such as MM with few side effects. In an ongoing phase 1a study, bisthianostat treatment was well tolerated and no grade 3/4 nonhematological adverse events (AEs) had occurred together with good pharmacokinetics profiles in eight patients with relapsed or refractory MM (R/R MM). The overall single-agent efficacy was modest, stable disease (SD) was identified in four (50%) patients at the end of first dosing cycle (day 28). These preliminary in-patient results suggest that bisthianostat is a promising HDACi drug with a comparable safety window in R/R MM, supporting for its further phase 1b clinical trial in combination with traditional MM therapies.
WOS关键词BELINOSTAT PXD101 ; HDAC-INHIBITOR ; II TRIAL ; PANOBINOSTAT ; VORINOSTAT ; BORTEZOMIB ; CHIDAMIDE ; PLASMA ; SAFETY ; SB939
资助项目Personalized Medicines-Molecular Signature-based Drug Discovery and Development ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020106] ; National Science and Technology Major Project of China[2018ZX09711002-011-006] ; Science and Technology Commission of Shanghai Municipality[19431906400] ; Science and Technology Development Foundation of Shanghai Pudong New Area Health and Family Planning Commission[PW2015E-1] ; Shanghai Three-Year Action Plan to Further Accelerate the Development of Traditional Chinese Medicine[ZY3-CCCX-3-3037]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000680352100002
出版者NATURE PUBLISHING GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/298280]  
专题新药研究国家重点实验室
通讯作者Nan, Fa-jun; Li, Jia; Hou, Jian
作者单位1.Yantai Inst Mat Med, Yantai Key Lab Nanomed & Adv Preparat, Yantai 264000, Peoples R China
2.Shanghai Ctr Drug Metab & Pharmacokinet Res, Shanghai 201203, Peoples R China
3.Shanghai Jiao Tong Univ, Renji Hosp, Dept Hematol, Sch Med, Shanghai 200127, Peoples R China
4.Chinese Acad Sci, Natl Ctr New Drug Screening, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Zhou, Yu-bo,Zhang, Yang-ming,Huang, Hong-hui,et al. Pharmacodynamic, pharmacokinetic, and phase 1a study of bisthianostat, a novel histone deacetylase inhibitor, for the treatment of relapsed or refractory multiple myeloma[J]. ACTA PHARMACOLOGICA SINICA,2021:9.
APA Zhou, Yu-bo.,Zhang, Yang-ming.,Huang, Hong-hui.,Shen, Li-jing.,Han, Xiao-feng.,...&Hou, Jian.(2021).Pharmacodynamic, pharmacokinetic, and phase 1a study of bisthianostat, a novel histone deacetylase inhibitor, for the treatment of relapsed or refractory multiple myeloma.ACTA PHARMACOLOGICA SINICA,9.
MLA Zhou, Yu-bo,et al."Pharmacodynamic, pharmacokinetic, and phase 1a study of bisthianostat, a novel histone deacetylase inhibitor, for the treatment of relapsed or refractory multiple myeloma".ACTA PHARMACOLOGICA SINICA (2021):9.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。