title: CRA-026440: a potent, broad-spectrum, hydroxamic histone deacetylase inhibitor with antiproliferative and antiangiogenic activity in vitro and in vivo.
abstract: CRA-026440 is a novel, broad-spectrum, hydroxamic acid-based inhibitor of histone deacetylase (HDAC) that shows antitumor and antiangiogenic activities in vitro and in vivo preclinically. CRA-026440 inhibited pure recombinant isozymes HDAC1, HDAC2, HDAC3/SMRT, HDAC6, HDAC8, and HDAC10 in the nanomolar range. Treatment of cultured tumor cell lines grown in vitro with CRA-026440 resulted in the accumulation of acetylated histone and acetylated tubulin, leading to an inhibition of tumor cell growth and the induction of apoptosis. CRA-026440 inhibited ex vivo angiogenesis in a dose-dependent manner. CRA-026440 parenterally given to mice harboring HCT116 or U937 human tumor xenografts resulted in a statistically significant reduction in tumor growth. CRA-026440, when used in combination with Avastin, achieved greater preclinical efficacy in HCT 116 colorectal tumor model. Inhibition of tumor growth was accompanied by an increase in the acetylation of alpha-tubulin in peripheral blood mononuclear cells and an alteration in the expression of many genes in the tumors, including several involved in angiogenesis, apoptosis, and cell growth. These results reveal CRA-026440 to be a novel HDAC inhibitor with potent antitumor activity.
authors.affiliation: Celera Genomics, 180 Kimball Way, South San Francisco, CA 94080, USA. alex_cao001@hotmail.com
authors.forename: Z Alexander
authors.initials: ZA
authors.lastname: Cao
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Bass
authors.forename: Sriram
authors.initials: S
authors.lastname: Balasubramanian
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.forename: Brian
authors.initials: B
authors.lastname: Schultz
authors.forename: Erik
authors.initials: E
authors.lastname: Verner
authors.forename: Yuqin
authors.initials: Y
authors.lastname: Dai
authors.forename: Rafael A
authors.initials: RA
authors.lastname: Molina
authors.forename: Jack R
authors.initials: JR
authors.lastname: Davis
authors.forename: Shawn
authors.initials: S
authors.lastname: Misialek
authors.forename: Martin
authors.initials: M
authors.lastname: Sendzik
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Orr
authors.forename: Ling
authors.initials: L
authors.lastname: Leung
authors.forename: Ondine
authors.initials: O
authors.lastname: Callan
authors.forename: Peter
authors.initials: P
authors.lastname: Young
authors.forename: Stacie A
authors.initials: SA
authors.lastname: Dalrymple
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Buggy
mesh_terms: D000107:Acetylation; D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000235:genetics; D011064:Poly Adenosine Diphosphate Ribose / Q000009:adverse effects; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; C513933:CRA 026440; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; C468783:H2AX protein, human; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007211:Indoles; D014404:Tubulin; D011064:Poly Adenosine Diphosphate Ribose