Pharmacokinetic optimization of class-selective histone deacetylase inhibitors and identification of associated candidate predictive biomarkers of hepatocellular carcinoma tumor response.
Herein, we describe the pharmacokinetic optimization of a series of class-selective histone deacetylase (HDAC) inhibitors and the subsequent identification of candidate predictive biomarkers of hepatocellular carcinoma (HCC) tumor response for our clinical lead using patient-derived HCC tumor xenograft models. Through a combination of conformational constraint and scaffold hopping, we lowered the in vivo clearance (CL) and significantly improved the bioavailability (F) and exposure (AUC) of our HDAC inhibitors while maintaining selectivity toward the class I HDAC family with particular potency against HDAC1, resulting in clinical lead 5 (HDAC1 IC₅₀ = 60 nM, mouse CL = 39 mL/min/kg, mouse F = 100%, mouse AUC after single oral dose at 10 mg/kg = 6316 h·ng/mL). We then evaluated 5 in a biomarker discovery pilot study using patient-derived tumor xenograft models, wherein two out of the three models responded to treatment. By comparing tumor response status to compound tumor exposure, induction of acetylated histone H3, candidate gene expression changes, and promoter DNA methylation status from all three models at various time points, we identified preliminary candidate response prediction biomarkers that warrant further validation in a larger cohort of patient-derived tumor models and through confirmatory functional studies.
Roche R&D Center-China Ltd., 720 Cai Lun Road, Building 5, Pudong, Shanghai 201203, P. R. China. jwong@alum.mit.edu
Jason C
JC
Wong
Guozhi
G
Tang
Xihan
X
Wu
Chungen
C
Liang
Zhenshan
Z
Zhang
Lei
L
Guo
Zhenghong
Z
Peng
Weixing
W
Zhang
Xianfeng
X
Lin
Zhanguo
Z
Wang
Jianghua
J
Mei
Junli
J
Chen
Song
S
Pan
Nan
N
Zhang
Yongfu
Y
Liu
Mingwei
M
Zhou
Lichun
L
Feng
Weili
W
Zhao
Shijie
S
Li
Chao
C
Zhang
Meifang
M
Zhang
Yiping
Y
Rong
Tai-Guang
TG
Jin
Xiongwen
X
Zhang
Shuang
S
Ren
Ying
Y
Ji
Rong
R
Zhao
Jin
J
She
Yi
Y
Ren
Chunping
C
Xu
Dawei
D
Chen
Jie
J
Cai
Song
S
Shan
Desi
D
Pan
Zhiqiang
Z
Ning
Xianping
X
Lu
Taiping
T
Chen
Yun
Y
He
Li
L
Chen
D000813:Anilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D018899:CpG Islands; D004354:Drug Screening Assays, Antitumor; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008745:Methylation; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009368:Neoplasm Transplantation; D010865:Pilot Projects; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D059467:Transcriptome; D014183:Transplantation, Heterologous
D000813:Anilides; D054316:Biomarkers, Pharmacological; D056572:Histone Deacetylase Inhibitors; D009025:Morpholines; D011759:Pyrrolidines; D056284:Histone Deacetylase 1