Discovery of Selective Histone Deacetylase 6 Inhibitors Using the Quinazoline as the Cap for the Treatment of Cancer

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.