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HDAC6-IN-1 is a potent and selective inhibitor for HDAC6 with an IC50 of 17 nM and shows 25-fold and 200-fold selectivity relative to HDAC1 (IC50=422 nM) and HDAC8 (IC50=3398 nM), respectively.

HDAC6-IN-1 (Compound 23bb) presents low nanomolar antiproliferative effects against panel of cancer cell lines. The antiproliferative activity is ton human malignant melanoma A375 cells and cervical cancer HeLa cells, HDAC6-IN-1 shows the most potent activities with IC50 values of 50 and 49 nM on A375 and HeLa cells, respectively. The antiproliferative activities against 11 kinds of hematological tumors (myelomaU266, RPMI8226 cells, human leukemia MV4-11, K562 cells, and human B cell lymphoma Ramos cells) or solid tumors (ovarian cancer A2780s, SKOV-3 cells, breast cancer SKBR3 cells, liver cancer HepG2 cells, lung cancer H460, A549 cells, cervical cancer HeLa cells and colon cancer HCT116, HT29 cells) cell lines of the HDAC6-IN-1 are evaluated by MTT, and the SAHA and ACY-1215 are as positive control. HDAC6-IN-1 shows significant antiproliferative potential with the IC50 values ranging from 14 to 104 nM in these tumor cell lines[1].

HDAC6-IN-1 (Compound 23bb) reduces the tumor growth in both the hematological tumor MV4-11 xenograft model and solid tumor HCT116 xenograft model. The significant antitumor activities are observed by intravenous administration of HDAC6-IN-1 at 50 mg/kg on MV4-11 and HCT116 xenograft models. The growth of MV4-11 and HCT116 cancer cell xenografts is suppressed by 55.0% and 76.3% (percent of tumor mass change [TGI] values) after iv administration of HDAC6-IN-1 at 50 mg/kg. The HCT116 xenograft model is also established to investigate the antitumor activity of oral administration of HDAC6-IN-1. The TGI value of oral administration of HDAC6-IN-1 (25 mg/kg) on HCT116 xenograft model is 60.4%, which is superior to the SAHA group (100 mg/kg, 59.2%). Additionally, the body weight decrease is acceptable and no other adverse effects are observed upon treatment with HDAC6-IN-1. Low clearance (CL=7.008 L/kg per hour for iv, CL=12.877 L/kg per hour for po) and long terminal half-life (t1/2=7.658 h for iv, t1/2=9.62 h for po) are observed in HDAC6-IN-1. The oral bioavailability of HDAC6-IN-1 is excellent in rats and the bioavailability is up to 47.0%[1].

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