651058-97-8Relevant academic research and scientific papers
Design, synthesis, and biological evaluation of dual targeting inhibitors of histone deacetylase 6/8 and bromodomain BRPF1
Erdmann, Frank,Günther, Stefan,Ghazy, Ehab,Hügle, Martin,Herp, Daniel,Jung, Manfred,Morales, Elizabeth R.,Robaa, Dina,Romier, Christophe,Schmidt, Matthias,Schmidtkunz, Karin,Sippl, Wolfgang,Zeyen, Patrik
, (2020/06/03)
Histone modifying proteins, specifically histone deacetylases (HDACs) and bromodomains, have emerged as novel promising targets for anticancer therapy. In the current work, based on available crystal structures and docking studies, we designed dual inhibitors of both HDAC6/8 and the bromodomain and PHD finger containing protein 1 (BRPF1). Biochemical and biophysical tests showed that compounds 23a,b and 37 are nanomolar inhibitors of both target proteins. Detailed structure-activity relationships were deduced for the synthesized inhibitors which were supported by extensive docking and molecular dynamics studies. Cellular testing in acute myeloid leukemia (AML) cells showed only a weak effect, most probably because of the poor permeability of the inhibitors. We also aimed to analyse the target engagement and the cellular activity of the novel inhibitors by determining the protein acetylation levels in cells by western blotting (tubulin vs histone acetylation), and by assessing their effects on various cancer cell lines.
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.
Design, synthesis and evaluation of novel 2-(1H-imidazol-2-yl) pyridine Sorafenib derivatives as potential BRAF inhibitors and anti-tumor agents
Jiao, Yu,Xin, Bo-Tao,Zhang, Yanmin,Wu, Jianbing,Lu, Xiaolin,Zheng, Ying,Tang, Weifang,Zhou, Xiang
, p. 170 - 183 (2015/01/08)
A series of 2-(1H-imidazol-2-yl) pyridine derivatives (CLW01-CLW31) have been designed and synthesized, and they were screened for BRAF kinase inhibitory activity. Besides, their biological activities were evaluated in vitro and in vivo. All the compounds were reported for the first time, and compounds CLW14 and CLW27 displayed the most potent antiproliferative activity against cell line A375 in vitro, with IC50 values of 4.26 and 2.93 1/4M, respectively, which were comparable with the positive control Sorafenib. Those two compounds were further evaluated for the in vivo efficacy using an A375 xenograft nude mice model. The results showed that the growth of A375 cancer cells xenografts was suppressed by factors of 35.68% and 42.50% (percent tumor growth inhibition values) after intragastric (ig) administration of compound CLW14 and CLW27 at concentration of 50 mg/kg. Thus they may be promising lead compounds to be developed as an alternative for current Sorafenib therapy.
