SB939: a potent and orally active HDAC inhibitor for the treatment of colorectal cancer

B292 Histone deacetylases (HDAC) have emerged as new molecular targets for cancer therapy. Small molecule HDAC inhibitors have been developed and shown to induce tumor cell cytostasis, differentiation and apoptosis in experimental models and efficacy in clinical trials in various hematological malignancies following intravenous and/or oral administration. However, they have not shown promising activity in solid tumors, which may be due to their poor pharmacokinetic properties and dose-limiting toxicities that don’t allow adequate tumor exposure to the drug. SB939 is a novel HDAC inhibitor with improved metabolic, pharmacokinetic and pharmacological properties compared to other HDAC inhibitors currently in clinical trials1. The objective of this study was to characterize the efficacy of SB939 in models of colon cancer. RNA interference mediated knockdown of class I and class II HDACs in the human colorectal cancer cell line, HCT116, revealed important cancer relevant functions for both classes emphasizing the usefulness of pan-HDAC inhibitors for the treatment of colorectal cancer. SB939 selectively inhibits HDAC class I and II enzymes, with Ki values ranging from 16 to 247 nM and inhibits proliferation of colon cancer cell lines with IC50sin therange of 500 nM. In these cell lines, SB939 induced cell cycle arrest leading to apoptotic cell death and also increased acetylation of histone3 (H3) and tubulin, increased the expression of p21, and reduced phosphorylation of retinoblastoma protein (pRb). SB939 also induced apoptosis in primary cells isolated from colorectal cancer patient tumor specimens. SB939 has excellent pharmacokinetic properties and tolerability after oral administration in mice. In a subcutaneous human colorectal cancer (HCT116) xenograft model, SB939 significantly and dose-dependently inhibited tumor growth (%TGI values after once daily oral dosing at 25, 50, 75 and 100 mg/kg for 21 days were 37%, 61%, 76% and 97% respectively). SB939 increased the level of acetylation of H3 in the HCT116 tumor tissue for up to 24 h and reduced the number of perfused blood vessels in the tumors. In APCmin/+ mice, a transgenic mouse model of early stage colorectal cancer, SB939 significantly reduced tumor load in both small intestine and colon (by 46% and 55% respectively after a once daily oral dose of 50 mg/kg for 21 days). In contrast, 5FU (40 mg/kg i.p. once daily for 5 days every 2 weeks for 21 days) significantly reduced tumor load in the small intestine only (39%).
 In conclusion, our data show that SB939 is a potent, orally active anti-tumor drug with potential for the treatment of early and late stage colorectal cancer.
 1Kanda Sangthongpitag, Haishang Wang, Pauline Yeo, Liu Xin, Evelyn Goh, Lee Sun New, Peizi Zeng, Xiaofeng Wu, Changyong Hu, Tony Ng and Kantharaj Ethirajulu. ADME attributes of SB939, a best-in-class HDAC Inhibitor, and its PK/PD correlation in the Pharmacological Species. EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics Prague Congress Centre, 2006, Nov 7-10; Prague, Czech Republic, Abstract number 166