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Metal-based anticancer agents occupy a distinct chemical space due to their particular coordination geometry and reactivity. Despite the initial DNA-targeting paradigm for this class of compounds, it is now clear that they can also be tuned to target proteins in cells, depending on the metal and ligand scaffold. Since metallodrug discovery is dominated by phenotypic screenings, tailored proteomics strategies were crucial to identify and validate protein targets of several investigative and clinically advanced metal-based drugs. Here, such experimental approaches are discussed, which showed that metallodrugs based on ruthenium, gold, rhenium and even platinum, can selectively and specifically target proteins with clear-cut down-stream effects. Target identification strategies are expected to support significantly the mechanism-driven clinical translation of metal-based drugs., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Samuel M. Meier-Menches reports financial support was provided by Austrian Science Fund., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Activation kinetics of metallo-prodrugs control the types of possible interactions with biomolecules. The intact metallo-prodrug is able to engage with potential targets by purely non-covalent bonding, while the activated metallodrug can form additional coordination bonds. It is hypothesized that the additional coordinative bonding might be favourable with respect to the target selectivity of activated metallodrugs. Thus, a time-dependent shotgun proteomics study was conducted in HCT116 colon carcinoma cells with plecstatins, which are organoruthenium anticancer drug candidates. First, the target selectivity was evaluated in a time-dependent fashion, which accounted for their hydrolysis kinetics. The binding selectivity increased from 50- to 160-fold and the average specificity from 0.72 to 0.86, respectively, from the 2 h to the 4 h target profiling experiment. Target profiling after 19 h did not reveal significant enrichments, possibly due to deactivation of the probe via arene cleavage. Up to 450 interactors were identified in the target profiling experiments. A plecstatin analogue that substituted a hydrogen bond acceptor with a hydrogen bond donor abrogated the target selectivity for plectin in HCT116 whole cell lysates, underlining the necessity of this hydrogen bond acceptor for a strong interaction between plecstatin and plectin. Second, time-dependent response profiling experiments provided evidence that plecstatin-2 induced an integrated stress response (ISR) in HCT116 cell culture. The phosphorylation of eIF2α, a key mediator of the ISR, after 3 h treatment indicated that this perturbation was initiated by the intact plecstatin-2 prodrug, while the effects of plectin-targeting are mediated by activated plecstatin-2.

Anticancer metallodrugs based on ruthenium and osmium are among the most investigated and advanced non-platinum metallodrugs. Inorganic drug discovery with these agents has undergone considerable advances over the past two decades and has currently two representatives in active clinical trials. As many ruthenium and osmium metallodrugs are prodrugs, a key question to be addressed is how the molecular reactivity of such metal-based therapeutics dictates the selectivity and the type of interaction with molecular targets. Within this frame, this review introduces the field by the examples of the most advanced ruthenium lead structures. Then, global structure-activity relationships are discussed for ruthenium and osmium metallodrugs with respect to in vitro antiproliferative/cytotoxic activity and in vivo tumor-inhibiting properties, as well as pharmacokinetics. Determining and validating global mechanisms of action and molecular targets are still major current challenges. Moreover, significant efforts must be invested in screening in vivo tumor models that mimic human pathophysiology to increase the predictability for successful preclinical and clinical development of ruthenium and osmium metallodrugs.

The ruthenium‐based anticancer agent BOLD‐100/KP1339 has shown promising results in several in vitro and in vivo tumour models as well as in early clinical trials. However, its mode of action remains to be fully elucidated. Recent evidence identified stress induction in the endoplasmic reticulum (ER) and concomitant down‐modulation of HSPA5 (GRP78) as key drug effects. By exploiting the naturally formed adduct between BOLD‐100 and human serum albumin as an immobilization strategy, we were able to perform target‐profiling experiments that revealed the ribosomal proteins RPL10, RPL24, and the transcription factor GTF2I as potential interactors of this ruthenium(III) anticancer agent. Integrating these findings with proteomic profiling and transcriptomic experiments supported ribosomal disturbance and concomitant induction of ER stress. The formation of polyribosomes and ER swelling of treated cancer cells revealed by TEM validated this finding. Thus, the direct interaction of BOLD‐100 with ribosomal proteins seems to accompany ER stress‐induction and modulation of GRP78 in cancer cells. [ABSTRACT FROM AUTHOR]

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Organometallic metal(arene) anticancer agents require ligand exchange for their anticancer activity and this is generally believed to confer low selectivity for potential cellular targets. However, using an integrated proteomics-based target-response profiling approach as a potent hypothesis-generating procedure, we found an unexpected target selectivity of a ruthenium(arene) pyridinecarbothioamide (plecstatin) for plectin, a scaffold protein and cytolinker, which was validated in a plectin knock-out model in vitro. Plectin targeting shows potential as a strategy to inhibit tumor invasiveness as shown in cultured tumor spheroids while oral administration of plecstatin-1 to mice reduces tumor growth more efficiently in the invasive B16 melanoma than in the CT26 colon tumor model. [ABSTRACT FROM AUTHOR]

Copyright of Angewandte Chemie is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

In ihrer Zuschrift auf S. 5121 identifizieren Samuel M. Meier-Menches, Christopher Gerner et al. die ribosomalen Proteine RPL10, RPL24 und den Transkriptionsfaktor GTF2I als wahrscheinliche Zielproteine. Innentitelbild: Die Wechselwirkung mit ribosomalen Proteinen begleitet die Stressinduktion des Wirkstoffkandidaten BOLD-100/KP1339 im endoplasmatischen Retikulum (Angew. Keywords: Bioanorganische Chemie; Metalle in der Medizin; Multi-Omik; Ribosom; Ruthenium DE Bioanorganische Chemie Metalle in der Medizin Multi-Omik Ribosom Ruthenium 5006 5006 1 02/24/21 20210301 NES 210301 B Ein Multiomics-Ansatz b , der Proteomik, Transkriptomik und Bildgebung umfasst, wurde angewendet, um die Wirkungsweise des Antikrebs-Ruthenium(III)-Wirkstoffkandidaten BOLD-100 umfassend zu untersuchen. [Extracted from the article]

Metallhaltige Tumortherapeutika werden oft als Prodrugs mit absichtlich geringer Selektivität konzipiert. Dagegen beschreiben S. M. Meier, C. Gerner et al. in der Zuschrift auf S. 8379 die unerwartet große Selektivität eines metallorganischen Ruthenium(II)‐Komplexes, der mit einer Kombination Proteomik‐basierter Methoden, dem Ziel‐Antwort‐Profiling, erhalten wurde. Plectin wurde als zentrale zelluläre Zielverbindung identifiziert. Das Plectin‐Targeting wechselwirkt mit dem Mikrotubulinetzwerk und könnte daher zur Krebsbekämpfung genutzt werden. [ABSTRACT FROM AUTHOR]

The ruthenium drug and GRP78 inhibitor KP1339/IT-139 has already demonstrated promising anticancer activity in a phase I clinical trial. This study aimed to identify mechanisms underlying increased sensitivity to KP1339 treatment. Based on a screen utilizing 23 cell lines, a small panel was selected to compare KP1339-sensitive and low-responsive models. KP1339 sensitivity was neither based on differences in ruthenium accumulation, nor sensitivity to oxidative stress or constituents of KP1339 (ruthenium chloride and indazole). Subsequently, the biochemical response to KP1339 was analyzed using whole genome expression arrays indicating that, while sensitive cell lines were characterized by "response to chemical stimuli" and "regulation of cell death", low-responsive cells preferentially activated pathways controlling cell cycle, DNA repair, and metabolism. Cell culture experiments confirmed that, while low-responsive cells executed cell cycle arrest in G2 phase, pronounced apoptosis induction via activation of caspase 8 was found in sensitive cells. Cell death induction is based on a unique disruption of the ER homeostasis by depletion of key cellular chaperones including GRP78 in combination with enhanced KP1339-mediated protein damage. [ABSTRACT FROM AUTHOR]