👤 Johannes Karges

Abstract Most clinically used chemotherapeutic agents act by inducing apoptosis. However, their clinical effectiveness is often limited by poor therapeutic efficacy and the rapid development of drug resistance. In contrast, oncosis, as an inflammatory form of cell death independent of adenosine triphosphate (ATP) and apoptotic pathways, exhibits unique advantages in overcoming tumor drug resistance and regulating anti‐tumor immune responses. Herein, we present the first iridium(III)‐based immunogenic oncosis inducers designed to concurrently induce oncosis and activate the cGAS–STING pathway, thereby bridging chemotherapy with immunotherapy. Through a bioisosteric design strategy, we identified benzoselenazole and benzothiazole derivatives as key pharmacophores for triggering oncosis. These iridium(III)‐based oncosis‐inducers rapidly disrupt mitochondrial architecture, induce oxidative stress, and promote Ca(II) release, which subsequently activate calpain and porimin to initiate oncosis in multidrug‐resistant cancer cells. Transcriptomic profiling further revealed their ability to regulate actin cytoskeleton organization, modulate ABC transporter activity, and affect glycolysis/gluconeogenesis. Notably, the metal complexes induce mitochondrial swelling and mt‐DNA damage, leading to robust activation of the cGAS–STING innate immune pathway and eliciting a strong anticancer immune response. Based on these multimodal mechanisms, the Ir(III)‐based immunogenic oncosis inducers were able to effectively kill drug‐resistant cancer cells and enhance the anticancer immune response in tumor mouse models. Show less

Photodynamic therapy (PDT) is a promising strategy for head and neck squamous cell carcinoma (HNSCC), but the immune consequences of tumor cell death remain incompletely understood. We compared two ruthenium(II) polypyridine photosensitizers (PSs) in HNSCC models and found that both were potently phototoxic (nanomolar IC₅₀s), triggered diverse cell death pathways (including autophagy and ferroptosis), and promoted hallmark danger signals of immunogenic cell death (ICD). Strikingly, only one PS induced apoptosis and strong endoplasmic reticulum (ER) stress, yet paradoxically led to immune tolerance in vivo. Conversely, the PS that did not induce apoptotic cell death with milder stress responses resulted in a better antitumor immunity in vivo. These unexpected findings challenge the prevailing view that PDT-triggered apoptosis and ER stress are essential for ICD. Our study underscores the complexity of PDT-induced cell death balance and immunogenic signals and highlights the need to redefine ICD-inducing criteria for the rational design of next-generation PSs. Show less

Despite the widespread use of chemotherapeutic agents, their reliance on apoptosis often limits therapeutic efficacy and leads to drug resistance. To overcome these challenges, alternative cell death mechanisms such as cuproptosis have gained significant attention. While previous studies have primarily focused on incorporation of Cu into nanostructures, this work presents the first example of a molecular tripodal Cu(II) complex as a potent cuproptosis inducer. Herein, a series of tripodal Cu(II) complexes were chemically synthesized and biologically evaluated. The most promising compound demonstrated remarkable cytotoxicity in the low micromolar to nanomolar range. Mechanistic studies revealed that the compound catalytically produced hydroxyl radicals in the mitochondria of cancerous cells, causing protein oligomerization and the disruption of iron-sulfur cluster proteins, ultimately triggering cell death by cuproptosis. Contrary to traditional chemotherapeutic agents that cause reduction in tumor size, this compound induced the fragmentation of three-dimensional tumor spheroids. Show less

Tumor metastases account for nearly 90% of cancer-related fatalities. To tackle this issue, chemotherapeutic agents that induce immunogenic cell death (ICD) are being investigated as promising candidates for metastatic cancer treatment. Herein, the chemical synthesis and biological evaluation of a novel Ga(III) complex with Schiff bases, [Ga((E)-1-((quinolin-8-ylimino)methyl)naphthalen-2-olato)₂][Cl], for potential use in combined chemotherapy and immunotherapy are reported. This compound exhibited broad cytotoxicity against human breast cancer, pancreatic cancer, cervical cancer cell lines, and the noncancerous human fibroblast cell line. Mechanistic investigations revealed that the compound triggers apoptosis and ICD hallmarks, such as translocation of calreticulin, phosphorylation of eIF2α, migration of high mobility group protein 1, and release of adenosine triphosphate. Deeper biological assessment using multicellular tumor spheroids of cervical cancer cell lines, a solid tumor model, demonstrated successful eradication at micromolar concentrations. This study presents one of the few reported Ga(III) complexes capable of inducing immunogenic cell death. Show less

This study presents the chemical synthesis and biological evaluation of a series of gold(I)-N-heterocyclic carbene complexes as potential anticancer agents. The compounds demonstrated broad activity against various cancer cell lines, exhibiting cytotoxicity in the low micromolar range. Mechanistic investigations revealed that these complexes preferentially accumulate in the mitochondria of cancer cells, where they induce the generation of reactive oxygen species and lipid peroxides, ultimately triggering ferroptosis. Further studies in multicellular tumor spheroids confirmed the compounds' ability to penetrate three-dimensional cellular structures and effectively eradicate them at low micromolar concentrations. This work represents the first known example of a gold(I)-N-heterocyclic carbene complex inducing ferroptosis, expanding the therapeutic potential of gold(I)-based metallodrugs. Show less

Interest in covalent enzyme inhibitors as therapeutic agents has seen a recent resurgence. Covalent enzyme inhibitors typically possess an organic functional group that reacts with a key feature of the target enzyme, often a nucleophilic cysteine residue. Herein, the application of small, modular Re^V complexes as inorganic cysteine-targeting warheads is described. These metal complexes were found to react with cysteine residues rapidly and selectively. To demonstrate the utility of these Re^V complexes, their reactivity with SARS-CoV-2-associated cysteine proteases is presented, including the SARS-CoV-2 main protease and papain-like protease and human enzymes cathepsin B and L. As all of these proteins are cysteine proteases, these enzymes were found to be inhibited by the Re^V complexes through the formation of adducts. These findings suggest that these Re^V complexes could be used as a new class of warheads for targeting surface accessible cysteine residues in disease-relevant target proteins. Show less

Computational modeling of inhibitors for metalloenzymes in virtual drug development campaigns has proven challenging. To overcome this limitation, a technique for predicting the binding pose of metal-binding pharmacophores (MBPs) is presented. Using a combination of density functional theory (DFT) calculations and docking using a genetic algorithm, inhibitor binding was evaluated in silico and compared with inhibitor-enzyme cocrystal structures. The predicted binding poses were found to be consistent with the cocrystal structures. The computational strategy presented represents a useful tool for predicting metalloenzyme-MBP interactions. Show less

Bioisosteres are a useful approach to address pharmacokinetic liabilities and improve drug-like properties. Specific to developing metalloenzyme inhibitors, metal-binding pharmacophores (MBPs) have been combined with bioisosteres, to produce metal-binding isosteres (MBIs) as alternative scaffolds for use in fragment-based drug discovery (FBDD). Picolinic acid MBIs have been reported and evaluated for their metal-binding ability, pharmacokinetic properties, and enzyme inhibitory activity. However, their structural, electronic, and spectroscopic properties with metal ions other than Zn(II) have not been reported, which might reveal similarities and differences between MBIs and the parent MBPs. To this end, [M(TPA)(MBI)]⁺ (M = Ni(II) and Co(II), TPA = tris(2-pyridylmethyl)amine) is presented as a bioinorganic model system for investigating picolinic acid, four heterocyclic MBIs, and 2,2'-bipyridine. These complexes were characterized by X-ray crystallography as well as NMR, IR, and UV-vis spectroscopies, and their magnetic moments were accessed. In addition, [(Tp^Ph,Me)Co(MBI)] (Tp^Ph,Me = hydrotris(3,5-phenylmethylpyrazolyl)borate) was used as a second model compound, and the limitations and attributes of the two model systems are discussed. These results demonstrate that bioinorganic model complexes are versatile tools for metalloenzyme inhibitor design and can provide insights into the broader use of MBIs. Show less

Fluorescence imaging is a powerful tool in biomedical research. It has been frequently used to uncover or better understand physiological mechanisms in disease-related processes such as cancer. The majority of chromophores used for imaging are based on a 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) scaffold. However, their applications are limited due to their poor water solubility as well as poor cancer cell selectivity. To circumvent these drawbacks, we present herein the use of bis(dipyrrinato)zinc(II) complexes. As this class of compounds is associated with a quenching effect of the excited state in water, the lead compound of this study (3) was encapsulated in a polymer matrix with biotin as a targeting moiety (3-NP). This encapsulation improved the water solubility, overcame the quenching effects in water, as well as allowed selective accumulation in the lysosomes with a bright fluorescence signal in monolayer cells as well as 3D multicellular tumor spheroids (MCTS). As a benefit from the biotin targeting moiety, the nanoparticles were majorly taken up by the sodium dependent multivitamin transporter (SMVT) which is overexpressed in various cancers cells and selectively accumulated in cancerous cells over noncancerous cells. Show less