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All total 26 Articles be found
All total 26 Articles be found4-Acyl Pyrrole Capped HDAC Inhibitors: A New Scaffold for Hybrid Inhibitors of BET Proteins and Histone Deacetylases as Antileukemia Drug Leads
Ahlert, Heinz,Bhatia, Sanil,Borkhardt, Arndt,Breit, Bernhard,Gunther, Stefan,Hansen, Finn K.,Hugle, Martin,Kraft, Fabian B.,Mishra, Pankaj,Schaker-Hubner, Linda,Schliehe-Diecks, Julian,Scholer, Andrea,Warstat, Robin
, p. 14620 - 14646 (2021/10/20)
Multitarget drugs are an emerging alternative to combination therapies. In three iterative cycles of design, synthesis, and biological evaluation, we developed a novel type of potent hybrid inhibitors of bromodomain, and extra-terminal (BET) proteins and histone deacetylases (HDACs) based on the BET inhibitor XD14 and well-established HDAC inhibitors. The most promising new hybrids, 49 and 61, displayed submicromolar inhibitory activity against HDAC1-3 and 6, and BRD4(1), and possess potent antileukemia activity. 49 induced apoptosis more effectively than the combination of ricolinostat and birabresib (1:1). The most balanced dual inhibitor, 61, induced significantly more apoptosis than the related control compounds 62 (no BRD4(1) affinity) and 63 (no HDAC inhibition) as well as the 1:1 combination of both. Additionally, 61 was well tolerated in an in vivo zebrafish toxicity model. Overall, our data suggest an advantage of dual HDAC/BET inhibitors over the combination of two single targeted compounds.
4-Acyl Pyrroles as Dual BET-BRD7/9 Bromodomain Inhibitors Address BETi Insensitive Human Cancer Cell Lines
Hügle, Martin,Regenass, Pierre,Warstat, Robin,Hau, Mirjam,Schmidtkunz, Karin,Lucas, Xavier,Wohlwend, Daniel,Einsle, Oliver,Jung, Manfred,Breit, Bernhard,Günther, Stefan
, p. 15603 - 15620 (2020/12/23)
Various malignant human diseases show disturbed signaling pathways due to increased activity of proteins within the epigenetic machinery. Recently, various novel inhibitors for epigenetic regulation have been introduced which promise a great therapeutic benefit. Inhibitors for the bromo- and extra-terminal domain (BET) family were of particular interest after inhibitors had shown a strong antiproliferative effect. More recently, the focus has increasingly shifted to bromodomains (BDs) outside the BET family. Based on previously developed inhibitors, we have optimized a small series of 4-acyl pyrroles, which we further analyzed by ITC, X-ray crystallography, selectivity studies, the NCI60 cell-panel, and GI50 determinations for several cancer cell lines. The inhibitors address both, BET and BRD7/9 BDs, with very high affinity and show a strong antiproliferative effect on various cancer cell lines that could not be observed for BD family selective inhibitors. Furthermore, a synergistic effect on breast cancer (MCF-7) and melanoma (SK-MEL-5) was proven.
Triazine-Based Cationic Leaving Group: Synergistic Driving Forces for Rapid Formation of Carbocation Species
Fujita, Hikaru,Kakuyama, Satoshi,Fukuyoshi, Shuichi,Hayakawa, Naoko,Oda, Akifumi,Kunishima, Munetaka
, p. 4568 - 4580 (2018/04/26)
A new triazine-based cationic leaving group has been developed for the acid-catalyzed alkylation of O- and C-nucleophiles. There are two synergistic driving forces, namely, stable C=O bond formation and charge-charge repulsive effects, involved in the rapid generation of the carbocation species in the presence of trifluoromethanesulfonic acid (～200 mol %). Considerable rate acceleration of benzylation, allylation, and p-nitrobenzylation was observed as compared to the reactions with less than 100 mol % of the acid catalyst. The triazine-based leaving group showed superior p-nitrobenzylation yield and stability in comparison to common leaving groups, trichloroacetimidate and bromide. A plausible reaction mechanism (the cationic leaving group pathway) was proposed on the basis of mechanistic and kinetic studies, NMR experiments, and calculations.
