10.1021/acs.jmedchem.5b01342.s002
Zhuang Yang
Zhuang
Yang
Taijin Wang
Taijin
Wang
Fang Wang
Fang
Wang
Ting Niu
Ting
Niu
Zhuowei Liu
Zhuowei
Liu
Xiaoxin Chen
Xiaoxin
Chen
Chaofeng Long
Chaofeng
Long
Minghai Tang
Minghai
Tang
Dong Cao
Dong
Cao
Xiaoyan Wang
Xiaoyan
Wang
Wei Xiang
Wei
Xiang
Yuyao Yi
Yuyao
Yi
Liang Ma
Liang
Ma
Jingsong You
Jingsong
You
Lijuan Chen
Lijuan
Chen
Discovery of Selective
Histone Deacetylase 6 Inhibitors
Using the Quinazoline as the Cap for the Treatment of Cancer
American Chemical Society
2015
SAHA
HDAC 6 inhibitor
nanomolar antiproliferative effects
Western blot analysis
HCT
vivo efficacy evaluations
MV
B cell lymphoma Romas xenografts
ACY
histone deacetylase 6
cancer cell lines
23 bb
Selective Histone Deacetylase 6 Inhibitors
IC
2015-10-06 00:00:00
Dataset
https://acs.figshare.com/articles/dataset/Discovery_of_Selective_Histone_Deacetylase_6_Inhibitors_Using_the_Quinazoline_as_the_Cap_for_the_Treatment_of_Cancer/2124883
Novel selective histone deacetylase
6 (HDAC6) inhibitors using
the quinazoline as the cap were designed, synthesized, and evaluated
for HDAC enzymatic assays. <i>N</i>-Hydroxy-4-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)butanamide, <b>23bb</b>, was the most potent selective inhibitor for HDAC6 with
an IC<sub>50</sub> of 17 nM and showed 25-fold and 200-fold selectivity
relative to HDAC1 and HDAC8, respectively. In vitro, <b>23bb</b> presented low nanomolar antiproliferative effects against panel
of cancer cell lines. Western blot analysis further confirmed that <b>23bb</b> increased acetylation level of α-tubulin in vitro. <b>23bb</b> has a good pharmacokinetic profile with oral bioavailability
of 47.0% in rats. In in vivo efficacy evaluations of colorectal HCT116,
acute myelocytic leukemia MV4-11, and B cell lymphoma Romas xenografts, <b>23bb</b> more effectively inhibited the tumor growth than SAHA
even at a 4-fold reduced dose or ACY-1215 at the same dose. Our results
indicated that <b>23bb</b> is a potent oral anticancer candidate
for selective HDAC6 inhibitor and deserves further investigation.