Detail of "404951-53-7"

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Molecular and cellular basis for the anti-proliferative effects of the HDAC inhibitor LAQ824

Some chemicals with cas registry numbers like 404951-53-7 and 148640-14-6 are also used. Molecular and cellular basis for the anti-proliferative effects of the HDAC inhibitor LAQ824. Atadja, Peter; Hsu, Meier; Kwon, Paul; Trogani, Nancy; Bhalla, Kapil; Remiszewski, Stacy (Department of Oncology Molecular and Cellular Biology, Novartis Institute for Biomedical Research, East Hanover, NJ 07936, USA). Novartis Foundation Symposium, 259(Reversible Protein Acetylation), 249-268 (English) 2004 John Wiley & Sons Ltd. CODEN: NFSYF7. ISSN: 1528-2511. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) We have developed a cinnamic hydroxamic class of histone deacetylase inhibitors of which a prototype was designated as NVP-LAQ824. NVP-LAQ824, inhibits historic deacetylase enzymic activities in vitro and transcriptionally activated the p21 promoter in reporter gene assays. When tested on a variety of solid tumor cell lines, NVP-LAQ824 exhibited selective anti-proliferative effects, inducing cell growth inhibition in some, while inducing cell death in others. To induce cell death, a min. of 16h exposure to NVP-LAQ824 is required. Flow cytometry studies revealed that both tumor cell lines and normal diploid fibroblasts arrested in the G2/M phase of the cell cycle after compd. treatment. However, an increased sub-G1 population at 48 h (reminiscent of apoptotic cells) was only obsd. in the cancer cell lines. Annexin V staining data confirmed that NVP-LAQ824 induced apoptosis in tumor cells, but not in normal cells. To relate HDAC inhibition to the antiproliferative effects of NVP-LAQ824, expression of HDAC 1 was inhibited using antisense and this was sufficient to activate p21 expression, hypophosphorylate Rb and inhibit cell growth. Furthermore, tumor cells treated with NVP-LAQ824 caused acetylation of HSP90 and degrdn. of its cargo oncoproteins. Finally, NVP-LAQ824 exhibited antitumor effects in a xenograft animal model. To det. if NVP-LAQ824 inhibited historic deacetylases in vivo, tumors treated with the drug were immunoblotted with an antibody specific for acetylated histories H3 and H4 and the results indicated increased historic H3 and H4 acetylation levels in NVP-LAQ824 treated cancer cells. Together, our data indicated that the activity of NVP-LAQ824 was consistent with its intended mechanism of action. This novel HDAC inhibitor is currently in clin. trials as an anticancer agent. .