Duocarmycin Analogues Target Aldehyde Dehydrogenase 1 in Lung Cancer Cells

Wirth, Tanja; Schmuck, Kianga; Tietze, Lutz F.; Sieber, Stephan A.

doi:10.1002/ange.201106334

Cited by 67 publications

(30 citation statements)

References 33 publications

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“…However, Wirth et al. demonstrated that the pulldown probe of the natural product duocarmycin SA (Table 1, entry 1) only isolates a second target protein (aldehyde dehydrogenase, ALDH1A1) for the natural product after incubation with living cells, as opposed to treatment with cell lysates which emphasizes that lysis condition might compromise binding of the target protein to the ligand 28…”

Section: Approaches To Target Identificationmentioning

confidence: 99%

Target Identification for Small Bioactive Molecules: Finding the Needle in the Haystack

et al. 2013

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Identification and confirmation of bioactive small-molecule targets is a crucial, often decisive step both in academic and pharmaceutical research. Through the development and availability of several new experimental techniques, target identification is, in principle, feasible, and the number of successful examples steadily grows. However, a generic methodology that can successfully be applied in the majority of the cases has not yet been established. Herein we summarize current methods for target identification of small molecules, primarily for a chemistry audience but also the biological community, for example, the chemist or biologist attempting to identify the target of a given bioactive compound. We describe the most frequently employed experimental approaches for target identification and provide several representative examples illustrating the state-of-the-art. Among the techniques currently available, protein affinity isolation using suitable small-molecule probes (pulldown) and subsequent mass spectrometric analysis of the isolated proteins appears to be most powerful and most frequently applied. To provide guidance for rapid entry into the field and based on our own experience we propose a typical workflow for target identification, which centers on the application of chemical proteomics as the key step to generate hypotheses for potential target proteins.

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Section: Approaches To Target Identificationmentioning

confidence: 99%

Target Identification for Small Bioactive Molecules: Finding the Needle in the Haystack

et al. 2013

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“…With the advances of mass spectrometry (MS) technologies, it is feasible to further identify the specific probe-labelling sites on protein targets. For example, the probe is directly incubated with purified proteins identified with ABPP and then labelled proteins are digested and desired peptides are analyzed by MS/MS11. Another promising method for binding site mapping performed in live cells is gel-free ABPP to identify probe-labelled peptides, including the selective enrichment and elution of probe-labelled peptide fragments121314.…”

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confidence: 99%

Mapping sites of aspirin-induced acetylations in live cells by quantitative acid-cleavable activity-based protein profiling (QA-ABPP)

Wang

Zhang

et al. 2015

Sci Rep

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Target-identification and understanding of mechanism-of-action (MOA) are challenging for development of small-molecule probes and their application in biology and drug discovery. For example, although aspirin has been widely used for more than 100 years, its molecular targets have not been fully characterized. To cope with this challenge, we developed a novel technique called quantitative acid-cleavable activity-based protein profiling (QA-ABPP) with combination of the following two parts: (i) activity-based protein profiling (ABPP) and iTRAQ™ quantitative proteomics for identification of target proteins and (ii) acid-cleavable linker-based ABPP for identification of peptides with specific binding sites. It is known that reaction of aspirin with its target proteins leads to acetylation. We thus applied the above technique using aspirin-based probes in human cancer HCT116 cells. We identified 1110 target proteins and 2775 peptides with exact acetylation sites. By correlating these two sets of data, 523 proteins were identified as targets of aspirin. We used various biological assays to validate the effects of aspirin on inhibition of protein synthesis and induction of autophagy which were elicited from the pathway analysis of Aspirin target profile. This technique is widely applicable for target identification in the field of drug discovery and biology, especially for the covalent drugs.

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“…Duocarmycins are known to bind and alkylate DNA in AT-rich regions of the minor groove, and induce cell death in a way dependent of DNA replication (Boger et al 1994;Tietze et al 2006;Tietze et al 2009) We checked that senescent cells were growth arrested at the time of the drug treatment (Sup Fig 1). This shows that the effect observed is not due to hyperreplication of cells during early stages of OIS and suggest that the prodrug might act by some of the alternative cytotoxic mechanisms described for duocarmycin dimers (Wirth et al 2012). Treatment with prodrug A induced caspase 3/7 activity on senescent cells (Fig 1c), and the selective death of this cells was prevented with a pan-caspase inhibitor (Fig 1d).…”

Section: A Galactose-modified Duocarmycin Prodrug With Senolytic Propmentioning

confidence: 73%

“…Duocarmycins are a group of antineoplastic agents with low picomolar potency. They are thought to act by binding and alkylating double stranded DNA in AT-rich regions of the minor groove, (Boger et al 1994;Tietze et al 2006;Tietze et al 2009), but alternative mechanisms of action have been proposed to account for the cytotoxic effects of duocarmycin dimers (Wirth et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Galactose-modified duocarmycin prodrugs as senolytics

Guerrero

Guiho

Herranz

et al. 2019

Preprint

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Senescence is a stable growth arrest that impairs the replication of damaged, old or preneoplastic cells, therefore contributing to tissue homeostasis. Senescent cells accumulate during ageing and are associated with diseases, such as cancer, fibrosis and many age-related pathologies. Recent evidence suggests that the selective elimination of senescent cells can be effective on the treatment of many of these senescence-associated diseases. A universal characteristic of senescent cells is that they display elevated activity of the lysosomal b-galactosidase this has been exploited as a marker for senescence (senescence-associated b-galactosidase activity). Consequently, we hypothesised that galactose-modified cytotoxic prodrugs will be preferentially processed by senescent cells, resulting in their selective killing. Here, we show that different galactose-modified duocarmycin (GMD) derivatives preferentially kill senescent cells. GMD prodrugs induce selective apoptosis of senescent cells in a lysosomal b-galactosidase (GLB1)-dependent manner. GMD prodrugs can eliminate a broad range of senescent cells in culture, and treatment with a GMD prodrug enhances the elimination of bystander senescent cells that accumulate upon whole body irradiation or doxorubicin treatment of mice. Moreover, taking advantage of a mouse model of human adamantinomatous craniopharyngioma (ACP), we show that treatment with a GMD pro-drug result selectively reduced the number of b-cateninpositive preneoplastic senescent cells, what could have therapeutic implications. In summary, the above results show that galactose-modified duocarmycin prodrugs behave as senolytics, suggesting that they could be used to treat a wide range of senescence-related pathologies. Guerrero et al. 4

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Duocarmycin Analogues Target Aldehyde Dehydrogenase 1 in Lung Cancer Cells

Cited by 67 publications

References 33 publications

Target Identification for Small Bioactive Molecules: Finding the Needle in the Haystack

Target Identification for Small Bioactive Molecules: Finding the Needle in the Haystack

Mapping sites of aspirin-induced acetylations in live cells by quantitative acid-cleavable activity-based protein profiling (QA-ABPP)

Galactose-modified duocarmycin prodrugs as senolytics

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