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 IC₅₀ 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

Development of Purine-Based Hydroxamic Acid Derivatives: Potent Histone Deacetylase Inhibitors with Marked in Vitro and in Vivo Antitumor Activities

In the present study, a series of novel histone deacetylase (HDAC) inhibitors using the morpholinopurine as the capping group were designed and synthesized. Several compounds demonstrated significant HDAC inhibitory activities and antiproliferative effects against diverse human tumor cell lines. Among them, compound <b>10o</b> was identified as a potent class I and class IIb HDAC inhibitor with good pharmaceutical profile and druglike properties. Western blot analysis further confirmed that <b>10o</b> more effectively increased acetylated histone H3 than panobinostat (LBH-589) and vorinostat (SAHA) at the same concentration in vitro. In in vivo efficacy evaluations of HCT116, MV4-11, Ramos, and MM1S xenograft models, <b>10o</b> showed higher efficacy than SAHA or LBH-589 without causing significant loss of body weight and toxicity. All the results indicated that <b>10o</b> could be a suitable candidate for treatment of both solid and hematological cancer