Docking and QSAR Studies of Aryl-valproic Acid Derivatives to Identify Antiproliferative Agents Targeting the HDAC8.

BACKGROUND: Histone deacetylase 8 (HDAC8) is a plausible target for the development of novel anticancer drugs using a metal-chelating group and hydrophobic moieties as pharmacophores. It is known that valproic acid (administered as its salt, sodium valproate; VPANa+) is an HDAC8 inhibitor characterized by its hydrophobic chains. Nevertheless, VPA is hepatotoxic and VPA analogues might be explored for less hepatotoxic antiproliferative compounds. METHOD: In this work, docking and QSAR studies of 500 aryl-VPA derivatives as possible HDAC8 inhibitors were performed in order to explore and select potential anti-proliferative compounds. Docking results identified π-π, hydrogen bonds as the most important noncovalent interactions between HDAC8 (PDB: 3F07) and the ligands tested, whereas Belm4 was the best QSAR descriptor and classified as a 2D-BCUT descriptor. RESULT: Based on theoretical studies, compound DAVP042 was synthesized and evaluated in vitro for its antiproliferative activities on several cancer cell lines (A549-lung, MCF-7-breast, HCT116-colon and U937- lymphoid tissue) in comparison to VPA, as well as for its inhibitory activity on HDAC8 using in vitro models. DAVP042 demonstrated to have antiproliferative activity on all cancer cell lines employed, not only suggesting that this compound should be further studied, but also demonstrating that the methodology herein employed is appropriated to identify new therapeutic candidates.

Recent therapeutic advances for treating medulloblastoma: focus on new molecular targets.

Medulloblastoma is the most common malignant brain tumor in children. This malignant tumor of the cerebellum commonly affects children and is believed to arise from the precursor cells of the external granule layer or neuroepithelial cells from the cerebellar ventricular zone of the developing cerebellum. The standard treatment, consisting of surgery, craniospinal radiotherapy and chemotherapy, still provides a poor overall survival for infants and young children. Furthermore, the dose of radiation that can be safely given without causing extensive neurocognitive and endocrinologic sequelae is limited. Therefore, understanding the oncogenic pathways that lead to medulloblastoma, as well as the identification of specific molecular targets with significant therapeutic implications in order to develop new strategies for therapy, is crucial to improve patient survival without substantially increasing toxicity. In this review, we discuss recent therapeutics for treating medulloblastoma, focusing on new molecular targets, as well as advances in translational studies for the treatment of this malignancy.

Sodium butyrate enhances the cytotoxic effect of antineoplastic drugs in human lymphoblastic T-cells.

Sodium butyrate (NaB), a potent histone deacetylase inhibitor, induces cell cycle arrest and apoptosis in malignant cells. We investigated the effects on cellular proliferation in vitro when combining NaB with antineoplastic drugs commonly used to treat leukemias. Our results demonstrate that NaB increases the cytotoxic effects of cytarabine and etoposide, but not of bleomycin, doxorubicin, vincristine or methotrexate. These data suggest that NaB is a promising adjuvant therapeutic agent for the treatment of lymphoblastic leukemias, and provides a basis for further studies in this field.