CETZOLE Analogs as Potent Ferroptosis Inducers and Their Target Identification Using Covalent/Affinity Probes.

Ferroptosis is a recently discovered cell death mechanism triggered by iron-dependent elevation of reactive oxygen species leading to lipid membrane peroxidation. We previously reported the development of a new class of ferroptosis inducers referred to as CETZOLEs with CC values in the low micromolar range. Structure-activity relationship study of these compounds led to the development of more potent analogs with CC values in the nanomolar range.

Regulation of Ferroptosis by Transcription Factor E2F1 and RB.

Tumor suppressor RB binds to E2F family proteins and modulates cell cycle progression. Cyclin dependent kinases (CDK) regulate the interaction of RB/E2F by phosphorylating RB. Previously, we have revealed that CDK2, RB and E2F inhibit ferroptosis.

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

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 and molecules to design the first-in-class dual mechanism hybrid molecules, which induce ferroptosis and inhibit HDAC proteins.

Rational design of metabolically stable HDAC inhibitors: An overhaul of trifluoromethyl ketones.

Epigenetic regulation of gene expression using histone deacetylase (HDAC) inhibitors is a promising strategy for developing new anticancer agents. The most common HDAC inhibitors are hydroxamates, which, though highly potent, have limitations due to their poor pharmacokinetic properties and lack of isoform selectivity. Trifluoromethylketones (TFMK) developed as alternatives to hydroxamates are rapidly metabolized to inactive trifluoromethyl alcohols in vivo, which prevented their further development as potential drug candidates.

Tunable Cysteine-Targeting Electrophilic Heteroaromatic Warheads Induce Ferroptosis.

Once considered potential liabilities, the modern era witnesses a renaissance of interest in covalent inhibitors in drug discovery. The available toolbox of electrophilic warheads is limited by constraints on tuning reactivity and selectivity. Following our work on a class of ferroptotic agents termed CETZOLEs, we discovered new tunable heterocyclic electrophiles which are capable of inducing ferroptosis.

Tumor suppressor p53 promotes ferroptosis in oxidative stress conditions independent of modulation of ferroptosis by p21, CDKs, RB, and E2F.

p53 is a well-established critical cell cycle regulator. By inducing transcription of the gene encoding p21, p53 inhibits cyclin-dependent kinase (CDK)-mediated phosphorylation of cell cycle inhibitor retinoblastoma (RB) proteins. Phosphorylation of RB releases E2F transcription factor proteins that transactivate cell cycle-promoting genes.

Identification and initial characterization of a potent inhibitor of ferroptosis.

Ferroptosis is a form of iron-dependent cell death characterized by elevated lipid peroxides and reactive oxygen species (ROS). Glutathione (GSH) plays an essential role in scavenging ROS to maintain cell viability and acts as a cofactor of GSH peroxidase 4 (GPX4) that protects lipids from oxidation. We have previously described a novel class of small molecules that induce ferroptosis in certain types of cancer cells.

Small-Molecule Ferroptotic Agents with Potential to Selectively Target Cancer Stem Cells.

Effective management of advanced cancer requires systemic treatment including small molecules that target unique features of aggressive tumor cells. At the same time, tumors are heterogeneous and current evidence suggests that a subpopulation of tumor cells, called tumor initiating or cancer stem cells, are responsible for metastatic dissemination, tumor relapse and possibly drug resistance. Classical apoptotic drugs are less effective against this critical subpopulation.