Aubry K Miller

Aubry K Miller
German Cancer Research Center | DKFZ · Research Group Cancer Drug Development

About

77
Publications
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1,238
Citations
Citations since 2016
55 Research Items
783 Citations
2016201720182019202020212022050100150
2016201720182019202020212022050100150
2016201720182019202020212022050100150
2016201720182019202020212022050100150

Publications

Publications (77)
Article
Pancreatic cancer has the lowest survival rate of all common cancers due to late diagnosis and limited treatment options. Serine hydrolases are known to mediate cancer progression and metastasis through initiation of signaling cascades and cleavage of extracellular matrix proteins, and the kallikrein-related peptidase (KLK) family of secreted serin...
Article
Full-text available
Correction for ‘Scalable synthesis and structural characterization of reversible KLK6 inhibitors’ by Andreas Baumann et al. , RSC Adv. , 2022, 12 , 26989–26993, https://doi.org/10.1039/D2RA04670A.
Article
We report the first well-characterized selective chemical probe for histone deacetylase 10 (HDAC10) with unprecedented selectivity over other HDAC isozymes. HDAC10 deacetylates polyamines and has a distinct substrate specificity, making it unique among the 11 zinc-dependent HDAC hydrolases. Taking inspiration from HDAC10 polyamine substrates, we sy...
Article
Full-text available
Scalable asymmetric syntheses of two kallikrein-related protease 6 (KLK6) inhibitors are reported. The inhibitors are assembled by linking enantiomerically enriched fragments via amide bond formation, followed by conversion of a cyano group to an amidine. One fragment, an amine, was prepared using the Ellman auxiliary, and a lack of clarity in the...
Article
Full-text available
Ferroptosis is a type of cell death caused by radical-driven lipid peroxidation, leading to membrane damage and rupture. Here we show that enzymatically produced sulfane sulfur (S⁰) species, specifically hydropersulfides, scavenge endogenously generated free radicals and, thereby, suppress lipid peroxidation and ferroptosis. By providing sulfur for...
Article
Full-text available
Cytosolic histone deacetylase-10 (HDAC10) specifically deacetylates the modified polyamine N8-acetylspermidine (N8-AcSpd). Although intracellular concentrations of N8-AcSpd are low, extracellular sources can be abundant, particularly in the colonic lumen. Extracellular polyamines, including those from the diet and microbiota, can support tumor grow...
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Drugs that target histone deacetylase (HDAC) entered the pharmacopoeia in the 2000s. However, some enigmatic phenotypes suggest off-target engagement. Here, we developed a quantitative chemical proteomics assay using immobilized HDAC inhibitors and mass spectrometry that we deployed to establish the target landscape of 53 drugs. The assay covers 9...
Article
Proteinmodifikationen. In ihrem Forschungsartikel (e202203684) zeigen Tobias P. Dick et al., dass Persulfid‐Addukte, die von häufig verwendeten Alkylierungsmitteln abstammen, unter biologisch relevanten Bedingungen instabil sind. Die Addukte wandeln sich in Thioether um, indem sie Sulfan‐Schwefel an nukleophile Akzeptoren abgeben.
Article
Protein Modifications. In their Research Article (e202203684), Tobias P. Dick et al. show that persulfide adducts derived from commonly used alkylating agents are unstable under biologically relevant conditions. The adducts convert to thioethers by losing sulfane sulfur to nucleophilic acceptors.
Article
Cytosolic histone deacetylase 10 (HDAC10) is specifically deacetylates the modified polyamine N8-acetylspermidine (N8-AcSpd). Although intracellular concentrations of N8-AcSpd are low, extracellular sources can be abundant, particularly in the colonic lumen. Extracellular polyamines, including those from the diet and microbiota, can support tumor g...
Article
We report asymmetric bioinspired total syntheses of the fungal metabolites emeriones A–C via stereoselective oxidations of two bicyclo[4.2.0]octadiene diastereomers. The central bicyclic scaffolds are prepared in an 8π/6π electrocyclization cascade of a stereodefined pentaene, which contains the fully assembled side chains of the emeriones. The ant...
Article
Full-text available
We report asymmetric bioinspired total syntheses of the fungal metabolites emeriones A–C via stereoselective oxidations of two bicyclo[4.2.0]octadiene diastereomers. The central bicyclic scaffolds are prepared in an 8π/6π electrocyclization cascade of a stereodefined pentaene, which contains the fully assembled side chains of the emeriones. The ant...
Preprint
Full-text available
S-acylation is a reversible posttranslational protein modification consisting of attachment of a fatty acid to a cysteine via a thioester bond. Research over the last few years has shown that a variety of different fatty acids, such as C16:0, C18:0 or C18:1, are used in cells to S-acylate proteins. We recently showed that GNAI proteins can be acyla...
Preprint
Full-text available
We report the first well-characterized selective chemical probe for histone deacetylase 10 (HDAC10) with unprecedented selectivity over other HDAC isozymes. HDAC10 deacetylates polyamines and has a distinct substrate specificity, making it unique among the 11 zinc-dependent HDAC hydrolases. Taking inspiration from HDAC10 polyamine substrates, we sy...
Article
Full-text available
Protein persulfides (R‐S‐SH) have emerged as a common post‐translational modification. Detection and quantitation of protein persulfides requires trapping with alkylating agents. Here we show that alkylating agents differ dramatically in their ability to conserve the persulfide’s sulfur‐sulfur bond for subsequent detection by mass spectrometry. The...
Article
Full-text available
Protein persulfides (R‐S‐SH) have emerged as a common post‐translational modification. Detection and quantitation of protein persulfides requires trapping with alkylating agents. Here we show that alkylating agents differ dramatically in their ability to conserve the persulfide’s sulfur‐sulfur bond for subsequent detection by mass spectrometry. The...
Preprint
Full-text available
Poorly antigenic small molecules pose challenges for the production of clinically efficacious antibodies. To address this, we have developed an immunization platform derived from the antigenic surface coat of the African trypanosome. Through sortase-based conjugation of antigens to the trypanosome surface coat protein variant surface glycoprotein (...
Article
Histone deacetylases (HDACs) are key epigenetic regulators involved in many diseases, especially cancer. Five HDAC inhibitors have been approved as drugs and many are in clinical trials. Among the 11 zinc‐dependent HDACs, HDAC10 has received relatively little attention by drug discovery campaigns, despite its involvement, e.g., in the pathogenesis...
Preprint
Full-text available
Histone deacetylases (HDACs) are important epigenetic regulators involved in many diseases, especially cancer. Five HDAC inhibitors have been approved for anticancer therapy and many are in clinical trials. Among the 11 zinc-dependent HDACs, HDAC10 has received relatively little attention by drug discovery campaigns, despite its involvement, e.g.,...
Preprint
Full-text available
We report an asymmetric bioinspired total synthesis of the fungal metabolites emeriones A–C via stereoselective late-stage epoxidation or endoperoxidation of two bicyclo[4.2.0]octadiene diastereomers. The central bicyclic scaffold is synthesized in an 8pi/6pi electrocyclization cascade of a stereodefined (E,E,Z,Z,E)-pentaene, which contains the ful...
Preprint
Full-text available
We report the first selective chemical probes for histone deacetylase 10 (HDAC10) with unprecedented selectivity over other HDAC isozymes. HDAC10 deacetylates polyamines and has a distinct substrate specificity, making it unique among the 11 zinc-dependent HDAC hydrolases. Taking inspiration from HDAC10 polyamine substrates, we systematically inser...
Preprint
We report the first selective chemical probes for histone deacetylase 10 (HDAC10) with unprecedented selectivity over other HDAC isozymes. HDAC10 deacetylates polyamines and has a distinct substrate specificity, making it unique among the 11 zinc-dependent HDAC hydrolases. Taking inspiration from HDAC10 polyamine substrates, we systematically inser...
Article
Kallikrein related peptidase 6 (Klk6) is a secreted serine protease highly expressed in oligodendrocytes and implicated in demyelinating conditions. To gain insights into the significance of Klk6 to oligodendrocyte biology, we investigated the impact of global Klk6 gene knockout on CNS developmental myelination using the spinal cord of male and fem...
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Full-text available
Nitrogen-inversion rates and diffusion coefficients were measured using 1H NMR for 14 drug-like molecules. The slow nitrogen-inversion rates interconverting the enantiomers of these molecules lay within a postulated intermediate range in terms of their ability to bind to proteins bounded by diffusion constraints, potentially affecting the availabil...
Article
Full-text available
The marbled crayfish ( Procambarus virginalis ) is a recently discovered freshwater crayfish species, which reproduces by apomictic parthenogenesis, resulting in a monoclonal, and all-female population. The animals were widely distributed through the aquarium trade and have established numerous stable wild populations through anthropogenic releases...
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Full-text available
Covalent attachment of C16:0 to proteins (palmitoylation) regulates protein function. Proteins are also S-acylated by other fatty acids including C18:0. Whether protein acylation with different fatty acids has different functional outcomes is not well studied. We show here that C18:0 (stearate) and C18:1 (oleate) compete with C16:0 to S-acylate Cys...
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Full-text available
We identified the gold(I)‐dithiocarbamate (dtc) complex [Au(N,N‐diethyl)dtc]2 as the active cytotoxic agent in the combination treatment of sodium aurothiomalate and disulfiram on a panel of cancer cell lines. In addition to demonstrating pronounced differential cytotoxicity to these cell lines, the gold complex showed no cross‐resistance in therap...
Article
The cytosolic class IIb histone deacetylase HDAC10 is an emerging target for drug design. As an inducer of autophagy, its selective inhibition suppresses the autophagic response that otherwise attenuates the efficacy of cytotoxic cancer chemotherapy drugs. HDAC10 is a zinc-dependent polyamine deacetylase exhibiting maximal catalytic activity agains...
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Full-text available
The NMR phenomenon of self-induced diastereomeric anisochronism (SIDA) was observed with an alcohol and an ester. The alcohol exhibited large concentration-dependent chemical shifts (δ’s), which initially led us to erroneously consider whether two enantiomers were in fact atropisomers. This highlights a potential complication for the analysis of ch...
Preprint
Histone deacetylases (HDACs) are important epigenetic regulators involved in many diseases, esp. cancer. First HDAC inhibitors have been approved for anticancer therapy and many are in clinical trials. Among the 11 zinc-dependent HDACs, HDAC10 has received relatively little attention by drug discovery campaigns, despite its involvement e.g. in the...
Article
Full-text available
We report the synthesis and evaluation of a class of selective multi‐target agents for the inhibition of HDAC6, HDAC8 and HDAC10. The concept for this study grew out of a structural analysis of the two selective inhibitors Tubastatin A (HDAC6/10) and PCI‐34051 (HDAC8), which we recognized share the same N ‐benzylindole core. Hybridization of the tw...
Preprint
The marbled crayfish (Procambarus virginalis) is a new freshwater crayfish species, which reproduces by apomictic parthenogenesis, resulting in a monoclonal, all-female population. The animals have become a popular source for nutritional protein in Madagacar and are increasingly being considered for commercial aquaculture. However, their potential...
Article
Histone deacetylase 6 (HDAC6) has gained popular attention for its wide participation in various pathological process recently. In this paper, a series of novel derivatives containing 2, 5-diketopiperazine (DKP) skeleton were developed as potent selective HDAC6 inhibitors (sHDAC6is). Most of these compounds exhibited low nanomolar IC50 values towar...
Article
Full-text available
Kallikrein‐related peptidase 6 (KLK6) is a secreted serine protease that belongs to the family of tissue kallikreins. Aberrant expression of KLK6 has been found in different cancers and neurodegenerative diseases, and KLK6 is currently studied as a potential target in these pathologies. We report a novel series of KLK6 inhibitors discovered in a hi...
Preprint
Full-text available
Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease that belongs to the family of tissue kallikreins. Aberrant expression of KLK6 has been found in different cancers and neurodegenerative diseases, and KLK6 is currently studied as a potential target in these pathologies. We report a novel series of KLK6 inhibitors discovered in a hi...
Article
The discovery of isozyme-selective histone deacetylase (HDAC) inhibitors is critical for understanding the biological functions of individual HDACs and for validating HDACs as drug targets. The isozyme HDAC10 contributes to chemotherapy resistance and has recently been described to be a polyamine deacetylase, but no studies toward selective HDAC10...
Preprint
The discovery of isozyme-selective histone deacetylase (HDAC) inhibitors is critical for understanding the biological functions of individual HDACs and for validating HDACs as clinical drug targets. The isozyme HDAC10 contributes to chemotherapy resistance via inhibition of autophagic flux and has recently been described to be a polyamine deacetyla...
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Full-text available
High histone deacetylase (HDAC) 8 and HDAC10 expression levels have been identified as predictors of exceptionally poor outcomes in neuroblastoma, the most common extracranial solid tumor in childhood. HDAC8 inhibition synergizes with retinoic acid treatment to induce neuroblast maturation in vitro and to inhibit neuroblastoma xenograft growth in v...
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Full-text available
Drug resistance is a leading cause for treatment failure in many cancers, including neuroblastoma, the most common solid extracranial childhood malignancy. Previous studies from our lab indicate that histone deacetylase 10 (HDAC10) is important for the homeostasis of lysosomes, i.e. acidic vesicular organelles involved in the degradation of various...
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Human tissue kallikrein (KLK) proteases are hormone-like signaling molecules with important functions in cancer pathophysiology. KLK-related peptidase 6 (KLK6), specifically, is highly up-regulated in several types of cancer, where its increased activity promotes cancer invasion and metastasis. This characteristic suggests KLK6 as an attractive tar...
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Full-text available
All isocitrate dehydrogenase (IDH) mutant solid neoplasms exhibit highly elevated levels of D-2-hydroxyglutarate (D-2HG). Detection of 2HG in tumor tissues currently is performed by gas or liquid chromatography-mass spectrometry (GC- or LC-MS) or biochemical detection. While these methods are highly accurate, a considerable amount of time for tissu...
Article
The molecular causes of type 2 diabetes (T2D) are not well understood. Both type 1 diabetes (T1D) and T2D are characterized by impaired insulin signaling and hyperglycemia. From analogy to T1D, insulin resistance and hyperglycemia are thought to also play causal roles in T2D. Recent clinical studies, however, found that T2D patients treated to main...
Article
The picturesque city of Heidelberg was host to last December′s conference, Drug Innovation in Academia, organized by the partner institutions of the Helmholtz Drug Research Initiative. Herein we summarize highlights of the two-day event, which brought together some of the brightest minds in both academic and private-sector drug research settings in...
Article
The use of small molecules to regulate cellular levels of specific proteins is poised to become a powerful technique in the coming years. Critical to the success of any project utilizing such an approach will be the ability to synthesize libraries of candidate small molecules for testing in cellular systems. Herein, we describe a practical synthesi...
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Full-text available
Introduction: Histone deacetylases (HDACs) are validated targets in antitumoral therapy, and five pan-HDAC inhibitors have been clinically approved to date. Dosage of these inhibitors is limited due to side effects (e.g. leukopenia, diarrhea, fatigue) mainly attributed to HDAC1, 2 and 3 inhibition. High HDAC8 and high HDAC10 co-expression correlate...
Article
Methionine aminopeptidases (MetAPs) are responsible for the co-translational cleavage of initiator methionines from nascent proteins. The MetAP2 subtype is up-regulated in many cancers, and selective inhibition of MetAP2 suppresses both vascularization and growth of tumors in animal models. The natural product fumagillin is a selective and potent i...
Article
Mitochondria are involved in a variety of cellular functions, including ATP production, amino acid and lipid biogenesis and breakdown, signalling and apoptosis. Mitochondrial dysfunction has been linked to neurodegenerative diseases, cancer and ageing. Although transcriptional mechanisms that regulate mitochondrial abundance are known, comparativel...
Article
The configuration at C6 of the epimeric bisulfite adducts of deoxyuridine was determined by means of NMR in conjunction with DFT calculations. The preferred conformations of the products were examined and it was found that the (6R)- and (6S)-epimers adopted predominantly different conformations—syn and anti, respectively, for the orientation of the...
Article
Full-text available
IDH mutations frequently occur in diffuse gliomas and result in a neo-enzymatic activity that results in reduction of alpha-ketoglutarate to d-2-hydroxyglutarate. In gliomas, the frequency of IDH1 mutations in codon 132 increases in the order R132L-R132S-R132G-R132C-R132H with R132H constituting more than 90% of all IDH1 mutations. We determined th...
Article
Sodium bisulfite promotes both the deformylative deamination of 5-formylcytosine (5fC) and the decarboxylative deamination of 5-carboxylcytosine (5caC; see picture). By coupling this bisulfite chemistry with selective oxidations of individual DNA bases, new methods allow, for the first time, the sequencing of 5-hydroxymethylcytosine (5hmC) with sin...
Article
Zwei neue Sequenzierungsmethoden nutzen die Tatsache, dass Natriumbisulfit sowohl die deformylierende Desaminierung von 5‐Formylcytosin (5fC) als auch die decarboxylierende Desaminierung von 5‐Carboxycytosin (5caC) bewirkt (siehe Bild). Durch Verbindung dieses Reaktionsverhaltens mit der selektiven Oxidation von DNA ermöglichen diese Methoden zum e...
Article
Mit zwei Additionen zum Produkt: Eine Totalsynthese von Bryostatin 16 zeichnet sich durch zwei Übergangsmetall-katalysierte Additionen aus. Die erste liefert Ring B und ermöglicht die Zuordnung seiner relativen Konfiguration; die zweite schließt den Makrocyclus mithilfe einer seltenen Isomerisierung. Die beiden Reaktionen benötigen weder Substratak...
Article
Adding up: A recent total synthesis of bryostatin 16 is highlighted by two transition-metal-catalyzed addition reactions. The first forges the B ring while establishing its relative stereochemistry. The second closes the macrocycle with a rare isomerization. These reactions neither require substrate activation nor do they generate byproducts. The p...