First-in-Class Dual Mechanism Ferroptosis-HDAC Inhibitor Hybrids

Abstract

HDAC inhibitors are an attractive class of cytotoxic agents for the design of hybrid molecules. Several HDAC hybrids have emerged over the years, but none combines HDAC inhibition with ferroptosis, a combination which is being extensively studied because it leads to enhanced cytotoxicity and attenuated neuronal toxicity. We combined the pharmacophores of SAHA and CETZOLE molecules to design the first-in-class dual mechanism hybrid molecules, which induce ferroptosis and inhibit HDAC proteins. The involvement of both mechanisms in cytotoxicity was confirmed by a series of biological assays. The cytotoxic effects were evaluated in a series of cancer and neuronal cell lines. Analogue HY-1 demonstrated the best cytotoxic profile with GI50 values as low as 20 nM. Although the increase in activity of the hybrids over the combinations is modest in cellular systems, they have the potential advantage of homogeneous spatiotemporal distribution in in vivo systems.

Oxidation Kinetics of Fluorescent Membrane Lipid Peroxidation Indicators

“…23,39,40 BODIPY C-11 is a boron-dipyrromethene dye and is widely used to detect LPO. 20,41−43 It has an advantage in enabling ratiometric determination of LPO, for example, in flow cytometry 44,45 as its overall fluorescence emission spectrum changes from red (590 nm) to green (520 nm) as it is oxidized (Figure 2B). 20,24,45 This spectral change is a composite result of multiple oxidation products at the conjugated diene.…”

Design, Synthesis, and Biological Evaluation for First GPX4 and CDK Dual Inhibitors

“…Induction of multiple modes of cell death is a promising therapeutic approach for cancers, and developing dual-target inhibitors is an effective strategy to achieve this goal. , Drug resistance is a common occurrence in cancer cells, and the high mesenchymal state in cancer cells is thought to be associated with resistance to multiple cancer therapies . It has been discovered that the GPX4-regulated LPO pathway is necessary for the therapy-resistant high mesenchymal cell state. , Disrupting the GPX4 signal pathway to trigger cellular ferroptosis could overcome drug resistance of colorectal cancer to oxaliplatin .…”

“…32 Although drug combination therapy can alleviate the deficiency of single drugs to a certain extent, it is difficult to obtain satisfactory efficacy due to the imparity in metabolic stability of different drugs during treatment. 18 To some extent, dual-target drugs could effectively prevent the occurrence of such problems. As a bifunctional molecule, it may have a more predictable pharmacokinetic (PK) profile compared to multiple molecules administered in combination.…”

“…To some extent, dual-target drugs could effectively prevent the occurrence of such problems. As a bifunctional molecule, it may have a more predictable pharmacokinetic (PK) profile compared to multiple molecules administered in combination. , Considering the crucial roles of GPX4 and CDK for remedying cancer, development of GPX4/CDK dual inhibitors would have great advantages in cancer therapy. ,− Hence, based on the structures of ML162 and IO, a series of dual GPX4/CDK inhibitors were designed and synthesized. Among all the compounds, B9 exhibited the strongest bioactivity and superior tumor-suppressive effect than ML162 or IO alone both in vitro and in vivo .…”

Discovery of Novel 1,2,3,4-Tetrahydrobenzofuro[2,3-c]pyridine Histone Deacetylase Inhibitors for Efficient Treatment of Hepatocellular Carcinoma

“…Histone deacetylases (HDACs) are an important component of epigenetic factors to catalyze the removal of acetyl and acyl groups from the modified ε-amino moiety of lysine in histone tails, thereby playing an essential role in the regulation of target gene expression. , The dysregulation of HDAC expression has been implicated in various cancer types, making HDACs attractive targets for cancer therapy. − Correspondingly, there were many endeavors that contributed to the development of HDAC inhibitors (HDACis) as a new therapeutic treatment, including pan-HDACis, − subtype-selective HDACiss, − and dual-target inhibitors based on HDAC. − Notably, five HDACis, namely, vorinostat (SAHA), belinostat, panobinostat, romidepsin, and chidamide, have been approved for the treatment of T-cell lymphoma and multiple myeloma (Figure ). Besides, several HDACis have been launched in clinical trials; for instance, abexinostat was in the phase III stage of a clinical trial for the treatment of renal carcinoma and lymphoma.…”