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.
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.
Imidazole-4-carboxamide (ICA), which is one of a group of “fairy chemicals” (FCs) that cause the fairy ring phenomena, has plant growth inhibitory activity. FCs have the potential as candidates for a new family of plant hormones as they have been found endogenously in all plant species tested, and show growth-regulating activity against the plants. While basic research on FCs is progressing, they are also expected to be applied not only to agrochemicals but also as pharmaceuticals. Derivatization of one of FCs, 2-azahypoxanthine (AHX) and the structure-activity relationship (SAR) studies have clarified its activity as a plant growth promoter. Yet, imidazole-4-carboxamide (ICA) has not been derivatized at all and SAR regarding its activity remains unknown. In this study, we synthesized the derivatives of ICA by direct C-H arylation of ICA precursors and evaluated its activity in rice. The 12 total compounds including the arylated ICAs and their precursors were evaluated for root and shoot elongation in rice, resulting in the discovery that a number of compounds unexpectedly have an elongation activity in the root and shoot.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.