Pharmacodynamic evaluation of the target efficacy of SB939, an oral HDAC inhibitor with selectivity for tumor tissue.

SB939 is an oral histone deacetylase (HDAC) inhibitor currently in phase II clinical trials potently inhibiting class I, II, and IV HDACs with favorable pharmacokinetic properties, resulting in tumor tissue accumulation. To show target efficacy, a Western blot assay measuring histone H3 acetylation (acH3) relative to a loading control was developed, validated on cancer cell lines, peripheral blood mononuclear cells (PBMC), and in animal tumor models. Exposure of cells to 60 nmol/L (22 ng/mL) SB939 for 24 hours was sufficient to detect an acH3 signal in 25 µg of protein lysate. AcH3 levels of liver, spleen, PBMCs, bone marrow and tumor were measured in BALB/c mice, HCT-116 xenografted BALB/c nude mice, or in SCID mice orthotopically engrafted with AML (HL-60) after oral treatment with SB939. AcH3 could only be detected after treatment. In all tissues, the highest signal detected was at the 3-hour time point on day 1. On day 15, the signal decreased in normal tissues but increased in cancerous tissues and became detectable in the bone marrow of leukemic mice. In all tissues, acH3 correlated with SB939 dose levels (r(2)=0.76-0.94). When applied to PBMCs from 30 patients with advanced solid malignancies in a phase I clinical trial, a dose-dependent (10-80 mg) increase in relative acH3 was observed 3-hour postdose on day 1, correlating with C(max) and AUC of SB939 concentrations in plasma (r=0.97, P=0.014). Our data show that the favorable pharmacokinetic and pharmacodynamic properties of SB939 are translated from preclinical models to patients.

SB939, a novel potent and orally active histone deacetylase inhibitor with high tumor exposure and efficacy in mouse models of colorectal cancer.

Although clinical responses in liquid tumors and certain lymphomas have been reported, the clinical efficacy of histone deacetylase inhibitors in solid tumors has been limited. This may be in part due to the poor pharmacokinetic of these drugs, resulting in inadequate tumor concentrations of the drug. SB939 is a new hydroxamic acid based histone deacetylase inhibitor with improved physicochemical, pharmaceutical, and pharmacokinetic properties. In vitro, SB939 inhibits class I, II, and IV HDACs, with no effects on other zinc binding enzymes, and shows significant antiproliferative activity against a wide variety of tumor cell lines. It has very favorable pharmacokinetic properties after oral dosing in mice, with >4-fold increased bioavailability and 3.3-fold increased half-life over suberoylanilide hydroxamic acid (SAHA). In contrast to SAHA, SB939 accumulates in tumor tissue and induces a sustained inhibition of histone acetylation in tumor tissue. These excellent pharmacokinetic properties translated into a dose-dependent antitumor efficacy in a xenograft model of human colorectal cancer (HCT-116), with a tumor growth inhibition of 94% versus 48% for SAHA (both at maximum tolerated dose), and was also effective when given in different intermittent schedules. Furthermore, in APC(min) mice, a genetic mouse model of early-stage colon cancer, SB939 inhibited adenoma formation, hemocult scores, and increased hematocrit values more effectively than 5-fluorouracil. Emerging clinical data from phase I trials in cancer patients indicate that the pharmacokinetic and pharmacologic advantages of SB939 are translated to the clinic. The efficacy of SB939 reported here in two very different models of colorectal cancer warrants further investigation in patients.