PMID- 34341512 OWN - NLM STAT- MEDLINE DCOM- 20220405 LR - 20221027 IS - 1745-7254 (Electronic) IS - 1671-4083 (Print) IS - 1671-4083 (Linking) VI - 43 IP - 4 DP - 2022 Apr TI - Pharmacodynamic, pharmacokinetic, and phase 1a study of bisthianostat, a novel histone deacetylase inhibitor, for the treatment of relapsed or refractory multiple myeloma. PG - 1091-1099 LID - 10.1038/s41401-021-00728-y [doi] AB - 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. CI - (c) 2021. The Author(s). FAU - Zhou, Yu-Bo AU - Zhou YB AD - National Center for New Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. AD - University of Chinese Academy of Sciences, Beijing, 100049, China. FAU - Zhang, Yang-Ming AU - Zhang YM AD - National Center for New Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. AD - University of Chinese Academy of Sciences, Beijing, 100049, China. AD - Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai, 264000, China. FAU - Huang, Hong-Hui AU - Huang HH AD - Department of Hematology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China. FAU - Shen, Li-Jing AU - Shen LJ AD - Department of Hematology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China. FAU - Han, Xiao-Feng AU - Han XF AD - Department of Hematology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China. FAU - Hu, Xiao-Bei AU - Hu XB AD - National Center for New Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. FAU - Yu, Song-da AU - Yu SD AD - National Center for New Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. AD - Shanghai Center for Drug Metabolism and Pharmacokinetics Research, Shanghai, 201203, China. FAU - Gao, An-Hui AU - Gao AH AD - National Center for New Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. FAU - Sheng, Li AU - Sheng L AD - National Center for New Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. FAU - Su, Ming-Bo AU - Su MB AD - National Center for New Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. FAU - Wei, Xiao-Li AU - Wei XL AD - National Center for New Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. FAU - Zhang, Yue AU - Zhang Y AD - National Center for New Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. FAU - Zhang, Yi-Fan AU - Zhang YF AD - National Center for New Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. AD - Shanghai Center for Drug Metabolism and Pharmacokinetics Research, Shanghai, 201203, China. FAU - Gao, Zhi-Wei AU - Gao ZW AD - National Center for New Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. AD - Shanghai Center for Drug Metabolism and Pharmacokinetics Research, Shanghai, 201203, China. FAU - Chen, Xiao-Yan AU - Chen XY AD - National Center for New Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. AD - University of Chinese Academy of Sciences, Beijing, 100049, China. AD - Shanghai Center for Drug Metabolism and Pharmacokinetics Research, Shanghai, 201203, China. FAU - Nan, Fa-Jun AU - Nan FJ AD - National Center for New Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. fjnan@simm.ac.cn. AD - University of Chinese Academy of Sciences, Beijing, 100049, China. fjnan@simm.ac.cn. AD - Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai, 264000, China. fjnan@simm.ac.cn. FAU - Li, Jia AU - Li J AD - National Center for New Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. jli@simm.ac.cn. AD - University of Chinese Academy of Sciences, Beijing, 100049, China. jli@simm.ac.cn. FAU - Hou, Jian AU - Hou J AD - Department of Hematology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China. houjian@medmail.com.cn. LA - eng PT - Clinical Trial, Phase I PT - Journal Article DEP - 20210802 PL - United States TA - Acta Pharmacol Sin JT - Acta pharmacologica Sinica JID - 100956087 RN - 0 (Histone Deacetylase Inhibitors) RN - 0 (Hydroxamic Acids) RN - 69G8BD63PP (Bortezomib) SB - IM MH - Acetylation MH - Animals MH - Antineoplastic Combined Chemotherapy Protocols MH - Bortezomib/therapeutic use MH - *Histone Deacetylase Inhibitors/pharmacokinetics/therapeutic use MH - Humans MH - Hydroxamic Acids/therapeutic use MH - Mice MH - *Multiple Myeloma/drug therapy/pathology PMC - PMC8976035 OTO - NOTNLM OT - HDAC inhibitor OT - antitumor drug OT - bisthianostat OT - multiple myeloma OT - pharmacodynamics OT - pharmacokinetics OT - phase 1a clinical trial COIS- The authors declare no competing interests. EDAT- 2021/08/04 06:00 MHDA- 2022/04/06 06:00 PMCR- 2021/08/02 CRDT- 2021/08/03 06:31 PHST- 2020/12/07 00:00 [received] PHST- 2021/06/27 00:00 [accepted] PHST- 2021/08/04 06:00 [pubmed] PHST- 2022/04/06 06:00 [medline] PHST- 2021/08/03 06:31 [entrez] PHST- 2021/08/02 00:00 [pmc-release] AID - 10.1038/s41401-021-00728-y [pii] AID - 728 [pii] AID - 10.1038/s41401-021-00728-y [doi] PST - ppublish SO - Acta Pharmacol Sin. 2022 Apr;43(4):1091-1099. doi: 10.1038/s41401-021-00728-y. Epub 2021 Aug 2.