TY - JOUR AU - Zhou Yu-bo AU - Zhang Yang-ming AU - Huang Hong-hui AU - Shen Li-jing AU - Han Xiao-feng AU - Hu Xiao-bei AU - Yu Song-da AU - Gao An-hui AU - Sheng Li AU - Su Ming-bo AU - Wei Xiao-li AU - Zhang Yue AU - Zhang Yi-fan AU - Gao Zhi-wei AU - Chen Xiao-yan AU - Nan Fa-jun AU - Li Jia AU - Hou Jian PY - 2022 TI - Pharmacodynamic, pharmacokinetic, and phase 1a study of bisthianostat, a novel histone deacetylase inhibitor, for the treatment of relapsed or refractory multiple myeloma JF - Acta Pharmacologica Sinica; Vol 43, No 4 (April 2022): Acta Pharmacologica Sinica Y2 - 2022 KW - N2 - 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·kg -1 ·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. UR - http://www.chinaphar.com/article/view/10546