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Deferasirox (Def), an orally administered iron‐chelating drug, has drawn significant interest in repurposing for anticancer application due to the elevated Fe demand by cancer cells. But there are also concerns about its severe off target health effects. Herein Cu(II) binding is studied as a potential off target interaction. The aqueous solution stability and speciation of the ternary complex Cu(Def)(pyridine) was studied by UV‐Vis and EPR spectroscopy, ESI‐mass spectrometry, and cyclic voltammetry under physiologically relevant conditions. The complex is observed to be a redox active, mononuclear Cu(II) complex in square planar geometry. UV‐Vis spectroscopy demonstrates that at pH 7.4 the complex is quite stable (ϵ337nm =10,820 M^−1cm^−1) with a log K=16.65±0.1. Cu scavenging from the Cu transporters ceruloplasmin and albumin was also studied. Def does not inhibit ceruloplasmin activity but forms a ternary Cu(II) complex at the bovine serum albumin ATCUN site. Cu(Def)(py) displays potent but nonselective cytotoxicity against A549 cancer and MRC‐5 noncancer lung cells but the potency of the ternary protein complex was more moderate. This work elucidates potential Def toxicity from Cu complexation in the body but also cytotoxic synergy between the metal and chelator that informs on new drug design directions. 

The discovery of regulated cell death (RCD) revolutionized chemotherapy. With caspase-dependent apoptosis initially being thought to be the only form of RCD, many drug development strategies aimed to synthesize compounds that turn on this kind of cell death. While yielding a variety of drugs, this approach is limited, given the acquired resistance of cancers to these drugs and the lack of specificity of the drugs for targeting cancer cells alone. The discovery of non-apoptotic forms of RCD is leading to new avenues for drug design. Evidence shows that ferroptosis, a relatively recently discovered iron-based cell death pathway, has therapeutic potential for anticancer application. Recent studies point to the interrelationship between iron and other essential metals, copper and zinc, and the disturbance of their respective homeostasis as critical to the onset of ferroptosis. Other studies reveal that several coordination complexes of non-iron metals have the capacity to induce ferroptosis. This collective knowledge will be assessed to determine how chelation approaches and coordination chemistry can be engineered to program ferroptosis in chemotherapy. 

Cardiovascular diseases (CVDs) are the leading cause of death worldwide and are heavily influenced by genetic factors. Genome-wide association studies have mapped >90% of CVD-associated variants within the noncoding genome, which can alter the function of regulatory proteins, such as transcription factors (TFs). However, due to the overwhelming number of single-nucleotide polymorphisms (SNPs) (>500,000) in genome-wide association studies, prioritizing variants for in vitro analysis remains challenging. In this work, we implemented a computational approach that considers support vector machine (SVM)-based TF binding site classification and cardiac expression quantitative trait loci (eQTL) analysis to identify and prioritize potential CVD-causing SNPs. We identified 1535 CVD-associated SNPs within TF footprints and putative cardiac enhancers plus 14,218 variants in linkage disequilibrium with genotype-dependent gene expression in cardiac tissues. Using ChIP-seq data from two cardiac TFs (NKX2-5 and TBX5) in human-induced pluripotent stem cell-derived cardiomyocytes, we trained a large-scale gapped k-mer SVM model to identify CVD-associated SNPs that altered NKX2-5 and TBX5 binding. The model was tested by scoring human heart TF genomic footprints within putative enhancers and measuring in vitro binding through electrophoretic mobility shift assay. Five variants predicted to alter NKX2-5 (rs59310144, rs6715570, and rs61872084) and TBX5 (rs7612445 and rs7790964) binding were prioritized for in vitro validation based on the magnitude of the predicted change in binding and are in cardiac tissue eQTLs. All five variants altered NKX2-5 and TBX5 DNA binding. We present a bioinformatic approach that considers tissue-specific eQTL analysis and SVM-based TF binding site classification to prioritize CVD-associated variants for in vitro analysis.