Spiruchostatin A is a class I specific histone deacetylase (HDAC) inhibitor with distinct pharmacodynamic properties compared to non-specific hydroxamate inhibitors.
Authors: Z. Alexander Cao, Kathryn E. Bass, Sriram Balasubramanian, Liang Liu, Yuchin Dai, Martin Sendzik, Rafael A. Molina, Christine J. Orr, Jack R. Davis, Ling Leung, Joseph J. Buggy, Stacie A. Dalrymple
Journal: Cancer Research (2006)

5047  Histone acetylation is one mechanism by which chromatin structure and its transcription is regulated. Histone acetylation and histone deacetylation, controlled by histone acetyltransferases and histone deacetylases (HDACs) respectively, play key roles in gene regulation. The inhibition of HDACs may result in chromatin remodeling, upregulation of key tumor suppressor genes and loss of fidelity during mitosis. Therefore, HDAC inhibitors are being evaluated in the clinic as anti-cancer therapeutics. CRA-026440 is a novel HDAC inhibitor. It displayed potent inhibition against human HDAC enzymes (Ki: 4-20 nM) and exhibited sub-μΜ growth inhibition against a panel of human cancer cell lines. CRA-026440 exhibited significant anti-tumor activity in vivo, both as a single agent and in combination with Avastin or 5FU. Here, we present data on CRA-026440: 1) The mechanism(s) of action:. A) Anti-angiogenesis: Examination of CRA-026440 in vitro in the rat aortic ring angiogenesis assay suggested possible anti-angiogenic activity. This activity was further corroborated by finding that the treatment of CRA-026440 in vivo had lead to the down-regulation of tumor angiogenesis-related genes such as VEGF and KDR. B) Tumor cell signaling. The effects of CRA-026440 on tumor cell proliferation and survival signals were examined in HCT 116. A panel of targets including caspase 3, B-catenin, CREB, HSP27, JNK, Jun, c-kit, Lck, Ikb, ERK, AKT, p38, p70, STAT3, IRS1, and EGFR were examined. Time-dependent induction of Erk and p70 (S6) phosphorylation, STAT3 protein level, and caspase 3 activation following the treatment of CRA-026440 was observed. 2) CRA-026440 was further examined in vivo in a panel of tumor xenograft models. Statistically significant efficacy was achieved in a U937 histiocytic lymphoma xenograft model and in an HCT 116 xenograft model. The CWR-22RV1 prostate tumor xenograft showed resistance to CRA-026440. The availability of xenograft models displaying a spectrum of sensitivities to CRA-026440 renders it possible to use such models for the identification and validation of efficacy bio-markers. In addition, the pharmacokinetic profile of CRA-026440 in xenograft model will be presented. In summary, CRA-026440, a potent broad-spectrum HDAC inhibitor, exhibited anti-proliferative and anti-angiogenic activities. Exploratory efforts on CRA-026440-related cellular signal transduction events may help shed light on the molecular response involved in CRA-026440’s anti-proliferative activities. Further examination may identify rational combination strategy that results in therapeutic synergy. With the continued examination of its mechanism of action, we hope to deliver targeted therapy by selecting rational dose regimen, combinatorial strategy and patient selection.