2021 marks the 30th anniversary of the revelation that cyclosporin A and FK506 act in a way previously not seen—as “molecular glues” that induce neo-protein–protein associations. As a torrent of new ...molecular-glue probes and medicines are fueling interest in this field, I explore the arc of this story.
2021 marks the 30th anniversary of the revelation that cyclosporin A and FK506 act in a way previously not seen—as “molecular glues” that induce neo-protein–protein associations. As a torrent of new molecular-glue probes and medicines are fueling interest in this field, I explore the arc of this story.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Ferroptosis is a unique type of non-apoptotic cell death resulting from the unrestrained occurrence of peroxidized phospholipids, which are subject to iron-mediated production of lethal oxygen ...radicals. This cell death modality has been detected across many organisms, including in mammals, where it can be used as a defense mechanism against pathogens or even harnessed by T cells to sensitize tumor cells toward effective killing. Conversely, ferroptosis is considered one of the main cell death mechanisms promoting degenerative diseases. Emerging evidence suggests that ferroptosis represents a vulnerability in certain cancers. Here, we critically review recent advances linking ferroptosis vulnerabilities of dedifferentiating and persister cancer cells to the dependency of these cells on iron, a potential Achilles heel for small-molecule intervention. We provide a perspective on the mechanisms reliant on iron that contribute to the persister cancer cell state and how this dependency may be exploited for therapeutic benefits.
Rodriguez et al. discuss how iron allows cells to acquire a drug-tolerant persister cancer state and how this addiction confers a high vulnerability to ferroptosis. This feature therefore opens up unprecedented opportunities to identify new predictors of ferroptosis sensitivity and provides the basis for the development of next-generation therapeutics.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Screening of small-molecule libraries is a productive method for identifying both chemical probes of disease-related targets and potential starting points for drug discovery. In this article, we ...focus on strategies such as diversity-oriented synthesis that aim to explore novel areas of chemical space efficiently by populating small-molecule libraries with compounds containing structural features that are typically under-represented in commercially available screening collections. Drawing from more than a decade's worth of examples, we highlight how the design and synthesis of such libraries have been enabled by modern synthetic chemistry, and we illustrate the impact of the resultant chemical probes and drug leads in a wide range of diseases.
Ferroptosis is an iron-dependent cell-death modality driven by oxidative phospholipid damage. In contrast to apoptosis, which enables organisms to eliminate targeted cells purposefully at specific ...times, ferroptosis appears to be a vulnerability of cells that otherwise use high levels of polyunsaturated lipids to their advantage. Cells in this high polyunsaturated lipid state generally have safeguards that mitigate ferroptotic risk. Since its recognition, ferroptosis has been implicated in degenerative diseases in tissues including kidney and brain, and is a targetable vulnerability in multiple cancers-each likely characterized by the high polyunsaturated lipid state with insufficient or overwhelmed ferroptotic safeguards. In this Perspective, we present progress toward defining the essential roles and key mediators of lipid peroxidation and ferroptosis in disease contexts. Moreover, we discuss gaps in our understanding of ferroptosis and list key challenges that have thus far limited the full potential of targeting ferroptosis for improving human health.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This Perspective explores molecular glues and bifunctional compounds—proximity-inducing compounds—and offers a framework to understand and exploit their similarity to hotspots, missense mutations, ...and posttranslational modifications (PTMs). This view is also shown to be relevant to intramolecular glues, where compounds induce contacts between distinct domains of the same protein. A historical perspective of these compounds is presented that shows the field has come full circle from molecular glues targeting native proteins, to bifunctionals targeting fusion proteins, and back to molecular glues and bifunctionals targeting native proteins. Modern screening methods and data analyses with pre-selected target proteins are shown to yield either cooperative molecular glues or bifunctional compounds that induce proximity, thereby enabling novel functional outcomes.
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In this Perspective, Dr. Stuart Schreiber provides a comprehensive insight into proximity-inducing compounds—molecular glues and bifunctional compounds, drawing analogies to hot spots, missense mutations, and posttranslational modifications—offering broader biological principles and a framework to exploit their similarity to modulate challenging therapeutic targets in novel ways.
Ferroptosis is a form of nonapoptotic cell death for which key regulators remain unknown. We sought a common mediator for the lethality of 12 ferroptosis-inducing small molecules. We used targeted ...metabolomic profiling to discover that depletion of glutathione causes inactivation of glutathione peroxidases (GPXs) in response to one class of compounds and a chemoproteomics strategy to discover that GPX4 is directly inhibited by a second class of compounds. GPX4 overexpression and knockdown modulated the lethality of 12 ferroptosis inducers, but not of 11 compounds with other lethal mechanisms. In addition, two representative ferroptosis inducers prevented tumor growth in xenograft mouse tumor models. Sensitivity profiling in 177 cancer cell lines revealed that diffuse large B cell lymphomas and renal cell carcinomas are particularly susceptible to GPX4-regulated ferroptosis. Thus, GPX4 is an essential regulator of ferroptotic cancer cell death.
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•Metabolomic profiling revealed GSH depletion as one mechanism of ferroptosis•Chemoproteomics identified GPX4 as a target for RSL3, a second ferroptosis inducer•GPX4 is a central regulator of ferroptosis, akin to bcl-2 in apoptosis•DLBCLs and renal cell carcinomas are sensitive to ferroptotic cell death
A chemoproteomic screen identifies a glutathione peroxidase as an essential regulator of a nonapoptotic form of cell death known as ferroptosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The development of effective small-molecule probes and drugs entails at least three stages: 1) a discovery phase, often requiring the synthesis and screening of candidate compounds, 2) an ...optimization phase, requiring the synthesis and analysis of structural variants, 3) and a manufacturing phase, requiring the efficient, large-scale synthesis of the optimized probe or drug. Specialized project groups tend to undertake the individual activities without prior coordination; for example, contracted (outsourced) chemists may perform the first activity while in-house medicinal and process chemists perform the second and third development stages, respectively. The coordinated planning of these activities in advance of the first small-molecule screen tends not to be undertaken, and each project group can encounter a bottleneck that could, in principle, have been avoided with advance planning. Therefore, a challenge for synthetic chemistry is to develop a new kind of chemistry that yields a screening collection comprising small molecules that increase the probability of success in all three phases. Although this transformative chemistry remains elusive, progress is being made. Herein, we review a newly emerging strategy in diversity-oriented small-molecule synthesis that may have the potential to achieve these challenging goals.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Direct control of mitochondrial function by mTOR Ramanathan, Arvind; Schreiber, Stuart L
Proceedings of the National Academy of Sciences - PNAS,
12/2009, Volume:
106, Issue:
52
Journal Article
Peer reviewed
Open access
mTOR is a central regulator of cellular growth and metabolism. Using metabolic profiling and numerous small-molecule probes, we investigated whether mTOR affects immediate control over cellular ...metabolism by posttranslational mechanisms. Inhibiting the FKBP12/rapamycin-sensitive subset of mTOR functions in leukemic cells enhanced aerobic glycolysis and decreased uncoupled mitochondrial respiration within 25 min. mTOR is in a complex with the mitochondrial outer-membrane protein Bcl-xl and VDAC1. Bcl-xl, but not VDAC1, is a kinase substrate for mTOR in vitro, and mTOR regulates the association of Bcl-xl with mTOR. Inhibition of mTOR not only enhances aerobic glycolysis, but also induces a state of increased dependence on aerobic glycolysis in leukemic cells, as shown by the synergy between the glycolytic inhibitor 2-deoxyglucose and rapamycin in decreasing cell viability.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
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