title: SB939, a novel potent and orally active histone deacetylase inhibitor with high tumor exposure and efficacy in mouse models of colorectal cancer.
abstract: 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.
authors.affiliation: S*Bio Pte. Ltd., #05-09 The Capricorn, Singapore Science Park II, Singapore. veronica_diermayr@sbio.com
authors.forename: Veronica
authors.initials: V
authors.lastname: Novotny-Diermayr
authors.forename: Kanda
authors.initials: K
authors.lastname: Sangthongpitag
authors.forename: Chang Yong
authors.initials: CY
authors.lastname: Hu
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Wu
authors.forename: Nina
authors.initials: N
authors.lastname: Sausgruber
authors.forename: Pauline
authors.initials: P
authors.lastname: Yeo
authors.forename: Gediminas
authors.initials: G
authors.lastname: Greicius
authors.forename: Sven
authors.initials: S
authors.lastname: Pettersson
authors.forename: Ai Leng
authors.initials: AL
authors.lastname: Liang
authors.forename: Yung Kiang
authors.initials: YK
authors.lastname: Loh
authors.forename: Zahid
authors.initials: Z
authors.lastname: Bonday
authors.forename: Kee Chuan
authors.initials: KC
authors.lastname: Goh
authors.forename: Hannes
authors.initials: H
authors.lastname: Hentze
authors.forename: Stefan
authors.initials: S
authors.lastname: Hart
authors.forename: Haishan
authors.initials: H
authors.lastname: Wang
authors.forename: Kantharaj
authors.initials: K
authors.lastname: Ethirajulu
authors.forename: Jeanette Marjorie
authors.initials: JM
authors.lastname: Wood
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D001682:Biological Availability; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D045325:HCT116 Cells; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat