Duocarmycin Analogues Target Aldehyde Dehydrogenase 1 in Lung Cancer Cells

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

doi:10.1002/anie.201106334

Cited by 76 publications

(35 citation statements)

References 31 publications

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“…Their molecular structure shows an indole moiety as DNA-binding component and a spirocyclopropylcyclohexadienone moiety as pharmacophore group that causes sequence-selective DNA alkylation (23). A recent controversial theory claims that duocarmycins act also by inhibiting aldehyde dehydrogenase 1, an enzyme target that plays important roles in the viability and detoxification of cancer cells (24)(25)(26). For ADCs applications, we have used duocarmycin analogues that had previously been shown to be more potent and more synthetically accessible than their naturally occurring counterpart (27).…”

Section: Introductionmentioning

confidence: 99%

Curative Properties of Noninternalizing Antibody–Drug Conjugates Based on Maytansinoids

et al. 2014

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It is generally thought that the anticancer efficacy of antibody-drug conjugates (ADC) relies on their internalization by cancer cells. However, recent work on an ADC that targets fibronectin in the tumor microenvironment suggests this may not be necessary. The alternatively spliced extra domains A and B (EDA and EDB) of fibronectin offer appealing targets for ADC development, because the antigen is strongly expressed in many solid human tumors and nearly undetectable in normal tissues except for the female reproductive system. In this study, we describe the properties of a set of ADCs based on an antibody targeting the alternatively spliced EDA of fibronectin coupled to one of a set of potent cytotoxic drugs (DM1 or one of two duocarmycin derivatives). The DM1 conjugate SIP(F8)-SS-DM1 mediated potent antitumor activity in mice bearing DM1-sensitive F9 tumors but not DM1-insensitive CT26 tumors. Quantitative biodistribution studies and microscopic analyses confirmed a preferential accumulation of SIP(F8)-SS-DM1 in the subendothelial extracellular matrix of tumors, similar to the pattern observed for unmodified antibody. Notably, we found that treatments were well tolerated at efficacious doses that were fully curative and compatible with pharmaceutical development. Our findings offer a preclinical proof-of-concept for curative ADC targeting the tumor microenvironment that do not rely upon antigen internalization. Cancer Res; 74(9); 2569-78. Ó2014 AACR.

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Section: Introductionmentioning

confidence: 99%

Curative Properties of Noninternalizing Antibody–Drug Conjugates Based on Maytansinoids

et al. 2014

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“…It binds to the minor groove of DNA and alkylates the nucleobase adenine, which leads to DNA double strand breaks and apoptosis. It has IC50 of ~10 pM against cancer cells [37]. Synthetic analogs of duocarmycin are available in modified and pro-drug forms for stability requirement before it reaches DNA.…”

Section: Cytotoxic Drugs and Mechanisms Of Actionmentioning

confidence: 99%

Conjugates of Small Molecule Drugs with Antibodies and Other Proteins

et al. 2014

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Conjugates of small molecule drugs with antibodies (ADCs) and with other proteins (protein-drug conjugates, PDC) are used as a new class of targeted therapeutics combining the specificity of monoclonal antibodies (mAbs) and other proteins with potent cytotoxic activity of small molecule drugs for the treatment of cancer and other diseases. A(P)DCs have three major components, antibody (targeting protein), linker and payload, the cytotoxic drug. Recently, advances in identifying targets, selecting highly specific mAbs of preferred isotypes, optimizing linker technology and improving chemical methods for conjugation have led to the approval of two ADCs by Food and Drug Administration (FDA) and more than 30 ADCs in advanced clinical development. However, the complex and heterogeneous nature of A(P)DCs often cause poor solubility, instability, aggregation and eventually unwanted toxicity. This article reviews the main components of A(P)DCs, and discusses the choices for drugs, linkers and conjugation methods currently used. Future work will need to focus on developments and strategies for overcoming such major problems associated with the A(P)DCs.

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“…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, Johnson, & Yun, 1994; Tietze et al, 2006; Tietze, Schuster, Krewer, & Schuberth, 2009), but alternative mechanisms of action have been proposed to account for the cytotoxic effects of duocarmycin dimers (Wirth, Schmuck, Tietze, & Sieber, 2012).…”

Section: Introductionmentioning

confidence: 99%

Galactose‐modified duocarmycin prodrugs as senolytics

et al. 2020

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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 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 β‐galactosidase, and this has been exploited as a marker for senescence (senescence‐associated β‐galactosidase activity). Consequently, we hypothesized 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 β‐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 treatment of mice. Moreover, taking advantage of a mouse model of adamantinomatous craniopharyngioma (ACP), we show that treatment with a GMD prodrug selectively reduced the number of β‐catenin‐positive preneoplastic senescent cells. In summary, the above results make a case for testing the potential of galactose‐modified duocarmycin prodrugs to treat senescence‐related pathologies.

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Duocarmycin Analogues Target Aldehyde Dehydrogenase 1 in Lung Cancer Cells

Cited by 76 publications

References 31 publications

Curative Properties of Noninternalizing Antibody–Drug Conjugates Based on Maytansinoids

Curative Properties of Noninternalizing Antibody–Drug Conjugates Based on Maytansinoids

Conjugates of Small Molecule Drugs with Antibodies and Other Proteins

Galactose‐modified duocarmycin prodrugs as senolytics

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