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 Vss 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.

Yu-bo Zhou;Yang-ming Zhang;Hong-hui Huang;Li-jing Shen;Xiao-feng Han;Xiao-bei Hu;Song-da Yu;An-hui Gao;Li Sheng;Ming-bo Su;Xiao-li Wei;Yue Zhang;Yi-fan Zhang;Zhi-wei Gao;Xiao-yan Chen;Fa-jun Nan;Jia Li;Jian Hou

National Center for New Drug Screening,State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China;University of Chinese Academy of Sciences,Beijing 100049,China;Yantai Key Laboratory of Nanomedicine&Advanced Preparations,Yantai Institute of Materia Medica,Yantai 264000,China;Department of Hematology,Renji Hospital,Shanghai Jiaotong University School of Medicine,Shanghai 200127,China;Shanghai Center for Drug Metabolism and Pharmacokinetics Research,Shanghai 201203,China

中国药理学报（英文版）

[1]Yu-bo Zhou;Yang-ming Zhang;Hong-hui Huang;Li-jing Shen;Xiao-feng Han;Xiao-bei Hu;Song-da Yu;An-hui Gao;Li Sheng;Ming-bo Su;Xiao-li Wei;Yue Zhang;Yi-fan Zhang;Zhi-wei Gao;Xiao-yan Chen;Fa-jun Nan;Jia Li;Jian Hou-.Pharmacodynamic,pharmacokinetic,and phase 1a study of bisthianostat,a novel histone deacetylase inhibitor,for the treatment of relapsed or refractory multiple myeloma)[J].中国药理学报（英文版）,2022(04):1091-1099

Pharmacodynamic,bisthianostat,Bisthianostat,bisthiazole,largazole,Vss,nonhematological

phase,1a,study,novel,histone,deacetylase,treatment,relapsed,refractory,multiple,myeloma,inhibitors,HDACis,have,been,intensively,studied,their,roles,potential,drug,targets,lymphomas,other,malignancies,pan,evolved,from,natural,Here,report,preclinical,alone,combination,bortezomib,MM,well,preliminary,first,human,findings,ongoing,dose,dependently,induced,acetylation,tubulin,H3,increased,PARP,cleavage,apoptosis,RPMI,cells,In,1S,xenograft,mouse,models,oral,administration,bid,days,inhibited,growth,Furthermore,displayed,synergistic,antitumor,against,vitro,vivo,Preclinical,showed,was,quickly,absorbed,moderate,bioavailability,tended,distribute,blood,value,This,distribution,parameter,might,beneficial,neoplasms,such,few,side,effects,tolerated,grade,adverse,events,AEs,had,occurred,together,good,pharmacokinetics,profiles,eight,patients,overall,single,agent,efficacy,modest,stable,disease,identified,four,dosing,cycle,These,results,suggest,that,promising,comparable,safety,window,supporting,its,further,1b,trial,traditional,therapies

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