Pharmacodynamic, pharmacokinetic, and phase 1a study of bisthianostat, a novel histone deacetylase inhibitor, for the treatment of relapsed or refractory multiple myeloma

doi:10.1038/s41401-021-00728-y

	Pharmacodynamic, pharmacokinetic, and phase 1a study of bisthianostat, a novel histone deacetylase inhibitor, for the treatment of relapsed or refractory multiple myeloma
	Zhou, Yu-bo 4,5; Zhang, Yang-ming 1,4,5; Huang, Hong-hui 3; Shen, Li-jing 3; Han, Xiao-feng 3; Hu, Xiao-bei 4; Yu, Song-da 2,4; Gao, An-hui 4; Sheng, Li 4; Su, Ming-bo 4
刊名	ACTA PHARMACOLOGICA SINICA
	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
DOI	10.1038/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.
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关键词	BELINOSTAT PXD101 ; HDAC-INHIBITOR ; II TRIAL ; PANOBINOSTAT ; VORINOSTAT ; BORTEZOMIB ; CHIDAMIDE ; PLASMA ; SAFETY ; SB939
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000680352100002
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/298280]
专题	中国科学院上海药物研究所
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.