Discovery of a Potent Chloroacetamide GPX4 Inhibitor with Bioavailability to Enable Target Engagement in Mice, a Potential Tool Compound for Inducing Ferroptosis <i>In Vivo</i>

Randolph, John T.; O'Connor, Matthew J; Han, Fei; Hutchins, Charles W.; Siu, Y Amy; Cho, Min; Zheng, Yunan; Hickson, Jonathan; Markley, Jana L.; Manaves, Vlasios; Algire, Mikkel A.; Baker, Kenton A; Chapman, Alex M; Gopalakrishnan, Sujatha M.; Panchal, Sanjay C.; Foster-Duke, Kelly D.; Stolarik, DeAnne; Kempf-Grote, Anita J; Dammeier, Darby; Fossey, Stacey L.; Sun, Qi; Sun, Chaohong; Shen, Yu; Dart, Michael J.; Kati, Warren M.; Lai, Albert; Firestone, Ari J.; Kort, Michael E.

doi:10.1021/acs.jmedchem.2c01415

Cited by 23 publications

(15 citation statements)

References 45 publications

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“…However, we suspect that many of these targets may not be pharmacologically relevant, as the reactive chloroacetamide moiety utilized in RSL3 is known to be highly reactive and broadly non-specific 38 . We thus further explored the targets of chloroacetamide based ferroptosis inducers with the RSL3 derivative Cpd24 39 , observing near identical results (Figure S3C). Thus, we performed protein class statistical overrepresentation analysis through the PANTHER classification system to narrow down our dataset.…”

Section: Resultsmentioning

confidence: 65%

Recharacterization of RSL3 reveals that the selenoproteome is a druggable target in colorectal cancer

DeAngelo,

Dziechciarz,

Solanki

et al. 2024

Preprint

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Ferroptosis is an iron-dependent, non-apoptotic form of cell death resulting from the accumulation of lipid peroxides. Colorectal cancer (CRC) accumulates high levels of intracellular iron and reactive oxygen species (ROS), thereby sensitizing cells to ferroptosis. The selenoprotein glutathione peroxidase (GPx4) is a key enzyme in the detoxification of lipid peroxides and can be inhibited by the compound (S)-RSL3 ([1S,3R]-RSL3). However, the stereoisomer (R)-RSL3 ([1R,3R]-RSL3), which does not inhibit GPx4, exhibits equipotent activity to (S)-RSL3 across a panel of CRC cell lines. Utilizing CRC cell lines with an inducible knockdown of GPx4, we demonstrate that (S)-RSL3 sensitivity does not align with GPx4 dependency. Subsequently, a biotinylated (S)-RSL3 was then synthesized to perform affinity purification-mass spectrometry (AP-MS), revealing that (S)-RSL3 acts as a pan-inhibitor of the selenoproteome, targeting both the glutathione and thioredoxin peroxidase systems as well as multiple additional selenoproteins. To investigate the therapeutic potential of broadly disrupting the selenoproteome as a therapeutic strategy in CRC, we employed further chemical and genetic approaches to disrupt selenoprotein function. The findings demonstrate that the selenoprotein inhibitor Auranofin can induce ferroptosis and/or oxidative cell death both in-vitro and in-vivo. Consistent with this data we observe that AlkBH8, a tRNA-selenocysteine methyltransferase required for the translational incorporation of selenocysteine, is essential for CRC growth. In summary, our research elucidates the complex mechanisms underlying ferroptosis in CRC and reveals that modulation of the selenoproteome provides multiple new therapeutic targets and opportunities in CRC.

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Section: Resultsmentioning

confidence: 65%

Recharacterization of RSL3 reveals that the selenoproteome is a druggable target in colorectal cancer

DeAngelo,

Dziechciarz,

Solanki

et al. 2024

Preprint

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“…Due to the structural characteristics, poor metabolic stability was a major defect of ML162. 57 Human liver microsomes were widely adopted for drug metabolism assays and evaluating ADME properties of drugs in vitro. Therefore, B9, ML162, and IO were selected to evaluate metabolic stability in human liver microsomes (Table 3).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Due to the structural characteristics, poor metabolic stability was a major defect of ML162 . Human liver microsomes were widely adopted for drug metabolism assays and evaluating ADME properties of drugs in vitro .…”

Section: Resultsmentioning

confidence: 99%

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

Zhu,

Cai,

Kong

et al. 2024

J. Med. Chem.

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The coexistence of ferroptosis and other modes of death has great advantages in the treatment of cancers. A series of glutathione peroxidase 4 (GPX4) and cyclin-dependent kinase (CDK) dual inhibitors were designed and synthesized, given the synergistic anticancer effect of ML162 (GPX4 inhibitor) in combination with indirubin-3′-oxime (IO) (CDK inhibitor).Compound B9 exhibited the highest potential cytotoxic activity against all four cell lines and displayed excellent inhibitory activity against GPX4 (IC 50 = 542.5 ± 0.9 nM) and selective inhibition of CDK 4/6 (IC 50 = 191.2 ± 8.7, 68.1 ± 1.4 nM). Mechanism research showed that B9 could simultaneously induce ferroptosis and arrest cells at the G1 phase in both MDA-MB-231 cells and HCT-116 cells. Compared with ML162 and IO, B9 showed much stronger cancer cell growth inhibition in vivo. These results proved that developing potent GPX4/CDK dual inhibitors is a promising strategy for the malignant cancer therapy.

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“…This may indicate that oxphos could be contributing to the altered ROS and redox state in these models. Further, inhibitors of GPX4 are currently being developed to induce ferroptosis, suggesting that targeting this pathway may be feasible in cancer ( Liu et al, 2022 ; Randolph et al, 2023 ). In contrast, FAO mediated ROS could be an adaptation in drug resistant cells.…”

Section: Therapy-induced Rewiring Of Mitochondrial Metabolism: Perman...mentioning

confidence: 99%

Rewiring of mitochondrial metabolism in therapy-resistant cancers: permanent and plastic adaptations

Pendleton,

Wang,

Echeverria

2023

Front. Cell Dev. Biol.

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Deregulation of tumor cell metabolism is widely recognized as a “hallmark of cancer.” Many of the selective pressures encountered by tumor cells, such as exposure to anticancer therapies, navigation of the metastatic cascade, and communication with the tumor microenvironment, can elicit further rewiring of tumor cell metabolism. Furthermore, phenotypic plasticity has been recently appreciated as an emerging “hallmark of cancer.” Mitochondria are dynamic organelles and central hubs of metabolism whose roles in cancers have been a major focus of numerous studies. Importantly, therapeutic approaches targeting mitochondria are being developed. Interestingly, both plastic (i.e., reversible) and permanent (i.e., stable) metabolic adaptations have been observed following exposure to anticancer therapeutics. Understanding the plastic or permanent nature of these mechanisms is of crucial importance for devising the initiation, duration, and sequential nature of metabolism-targeting therapies. In this review, we compare permanent and plastic mitochondrial mechanisms driving therapy resistance. We also discuss experimental models of therapy-induced metabolic adaptation, therapeutic implications for targeting permanent and plastic metabolic states, and clinical implications of metabolic adaptations. While the plasticity of metabolic adaptations can make effective therapeutic treatment challenging, understanding the mechanisms behind these plastic phenotypes may lead to promising clinical interventions that will ultimately lead to better overall care for cancer patients.

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Discovery of a Potent Chloroacetamide GPX4 Inhibitor with Bioavailability to Enable Target Engagement in Mice, a Potential Tool Compound for Inducing Ferroptosis In Vivo

Cited by 23 publications

References 45 publications

Recharacterization of RSL3 reveals that the selenoproteome is a druggable target in colorectal cancer

Recharacterization of RSL3 reveals that the selenoproteome is a druggable target in colorectal cancer

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

Rewiring of mitochondrial metabolism in therapy-resistant cancers: permanent and plastic adaptations

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