858124-10-4Relevant academic research and scientific papers
Synthesis, structure-activity relationships, cocrystallization and cellular characterization of novel smHDAC8 inhibitors for the treatment of schistosomiasis
Darwish, Salma,Erdmann, Frank,Ghazy, Ehab,Heimburg, Tino,Jung, Manfred,Lancelot, Julien,Pierce, Raymond,Robaa, Dina,Romier, Christophe,Schmidt, Matthias,Schmidtkunz, Karin,Shaik, Tajith B.,Simoben, Conrad V.,Sippl, Wolfgang,Truhn, Anne,Zeyen, Patrik
, (2021/08/17)
Schistosomiasis is a major neglected parasitic disease that affects more than 265 million people worldwide and for which the control strategy consists of mass treatment with the only available drug, praziquantel. In this study, we chemically optimized our previously reported benzhydroxamate-based inhibitors of Schistosoma mansoni histone deacetylase 8 (smHDAC8). Crystallographic analysis provided insights into the inhibition mode of smHDAC8 activity by the highly potent inhibitor 5o. Structure-based optimization of the novel inhibitors was carried out using the available crystal structures as well as docking studies on smHDAC8. The compounds were evaluated in screens for inhibitory activity against schistosome and human HDACs (hHDAC). The in vitro and docking results were used for detailed structure activity relationships. The synthesized compounds were further investigated for their lethality against the schistosome larval stage using a fluorescence-based assay. The most promising inhibitor 5o showed significant dose-dependent killing of the schistosome larvae and markedly impaired egg laying of adult worm pairs maintained in culture.
Structure-Based Design and Biological Characterization of Selective Histone Deacetylase 8 (HDAC8) Inhibitors with Anti-Neuroblastoma Activity
Heimburg, Tino,Kolbinger, Fiona R.,Zeyen, Patrik,Ghazy, Ehab,Herp, Daniel,Schmidtkunz, Karin,Melesina, Jelena,Shaik, Tajith Baba,Erdmann, Frank,Schmidt, Matthias,Romier, Christophe,Robaa, Dina,Witt, Olaf,Oehme, Ina,Jung, Manfred,Sippl, Wolfgang
, p. 10188 - 10204 (2018/01/10)
Histone deacetylases (HDACs) are important modulators of epigenetic gene regulation and additionally control the activity of non-histone protein substrates. While for HDACs 1-3 and 6 many potent selective inhibitors have been obtained, for other subtypes much less is known on selective inhibitors and the consequences of their inhibition. The present report describes the development of substituted benzhydroxamic acids as potent and selective HDAC8 inhibitors. Docking studies using available crystal structures have been used for structure-based optimization of this series of compounds. Within this study, we have investigated the role of HDAC8 in the proliferation of cancer cells and optimized hits for potency and selectivity, both in vitro and in cell culture. The combination of structure-based design, synthesis, and in vitro screening to cellular testing resulted in potent and selective HDAC8 inhibitors that showed anti-neuroblastoma activity in cellular testing.
Angiogenesis inhibitors identified by cell-based high-throughput screening: Synthesis, structure-activity relationships and biological evaluation of 3-[(E)-styryl]benzamides that specifically inhibit endothelial cell proliferation
Hada, Kihito,Suda, Atsushi,Asoh, Kohsuke,Tsukuda, Takuo,Hasegawa, Masami,Sato, Yasuko,Ogawa, Kotaro,Kuramoto, Shino,Aoki, Yuko,Shimma, Nobuo,Ishikawa, Tsutomu,Koyano, Hiroshi
, p. 1442 - 1460 (2012/04/17)
Proliferation of endothelial cells is critical for angiogenesis. We report orally available, in vivo active antiangiogenic agents which specifically inhibit endothelial cell proliferation. After identifying human umbilical vein endothelial cell (HUVEC) pr
