Discovery of Selective Histone Deacetylase 6 Inhibitors Using the Quinazoline as the Cap for the Treatment of Cancer YangZhuang WangTaijin WangFang NiuTing LiuZhuowei ChenXiaoxin LongChaofeng TangMinghai CaoDong WangXiaoyan XiangWei YiYuyao MaLiang YouJingsong ChenLijuan 2015 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.