Irreversible Inhibitors of Tissue Transglutaminase

Keillor, Jeffrey W.; Chabot, Nicolas; Roy, Isabelle; Mulani, Amina; Leogane, Olivier; Pardin, Christophe

doi:10.1002/9781118105771.ch10

Cited by 15 publications

(16 citation statements)

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“…14−17 Several classes of TG2 inhibitors have been reported, most of which are irreversible in nature. 18 In addition, we have reported potent and selective covalent inhibitors bearing an acrylamide warhead as in 1 (Figure 1). 19 Compound 1 has TG2 IC 50 of 0.11 μM; however, in vitro metabolism profiling studies identified plasma stability as an issue cautioning against in vivo evaluation.…”

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confidence: 99%

Irreversible 4-Aminopiperidine Transglutaminase 2 Inhibitors for Huntington's Disease

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Brookfield

Courtney

et al. 2012

ACS Med. Chem. Lett.

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A new series of potent TG2 inhibitors are reported that employ a 4-aminopiperidine core bearing an acrylamide warhead. We establish the structure−activity relationship of this new series and report on the transglutaminase selectivity and in vitro ADME properties of selected compounds. We demonstrate that the compounds do not conjugate glutathione in an in vitro setting and have superior plasma stability over our previous series. KEYWORDS: plasma stability, computer-aided drug design, SAR, acrylamides, Celiac disease, ADME T issue transglutaminase 2 (TG2) is a multifunctional enzyme primarily known for its calcium-dependent cross-linking activity via isopeptide bond formation.1 Less well-studied activities of TG2 include simple amidase, GTPase, ATPase, and protein disulfide isomerase activities.2−4 TG2 has been characterized in at least three forms, including open, 5 closed, 6 and an open-inactive form. 7 Genetic deletion of TG2 in mice suggests a role for TG2 activity in mitochondrial energy function.8 TG2 overactivity has been most closely associated with Celiac disease and Huntington's disease (HD), and there is growing support for roles in inflammation and cancer. 9−12 HD is an autosomal dominant, progressive neurodegenerative disease that is characterized clinically by motor, cognitive, and behavioral deficits. TG2 expression and transglutaminase activity have been shown to be increased in the brains of HD patients, 13 and in vitro and in vivo studies have implicated TG2 in HD pathophysiology. 14−17Several classes of TG2 inhibitors have been reported, most of which are irreversible in nature. 18 In addition, we have reported potent and selective covalent inhibitors bearing an acrylamide warhead as in 1 (Figure 1). 19 Compound 1 has TG2 IC 50 of 0.11 μM; however, in vitro metabolism profiling studies identified plasma stability as an issue cautioning against in vivo evaluation. Compound 1 was one of the examples showing better stability in plasma, having a half-life of 209 min in mouse plasma. Evidence supporting the acrylamide amide linkage as the site of metabolic instability was obtained by testing the plasma stability of aniline analogue 2 (Figure 1) and detecting its formation in plasma incubation of cyclopropylamide 1. Aniline 2 showed no indication of metabolism over a 24 h period in mouse plasma. The acrylamide warhead has been featured in several EGFR irreversible inhibitors that have progressed to clinical trials, 20 suggesting that this moiety is not especially susceptible to metabolism and enabling compounds to reach acceptable plasma exposures in vivo. Thus, we present here a structure−activity relationship (SAR) study of a new class of acrylamide-bearing TG2 inhibitors that show improved plasma stability.Our approach to stabilize the compounds to plasma exposure initially focused on replacing the problematic anilide with a more robust alkylamide. The compounds in Table 1 were prepared mainly to expand rapidly the SAR with respect to TG2 as this series of compounds still possessed ...

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confidence: 99%

Irreversible 4-Aminopiperidine Transglutaminase 2 Inhibitors for Huntington's Disease

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Brookfield

Courtney

et al. 2012

ACS Med. Chem. Lett.

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“…DHI inhibitors form a thioether bond with the TG active site cysteine [34], a modification that should be detectable by mass spectrometry. Since 3 appeared less effective in a solution cross-linking assay than the primary assay, it is necessary to confirm covalent modification of the active site cysteine.…”

Section: Resultsmentioning

confidence: 99%

“…Modeling combined with kinetic, SAR and structural studies may lead to more potent active site inhibitors of AgTG3. Future optimization could also include substitution of the DHI functional group with other cysteine-reactive functionalities [34]. …”

Section: Discussionmentioning

confidence: 99%

“…TGs are Ca2+-activated enzymes that rely on an active site cysteine to catalyze transamidation via a ‘ping-pong’ mechanism, in which the sulfhydryl attacks the glutamine group forming an acyl intermediate that is substituted by lysine (Figure 1A). The majority of TG inhibitors are tight, slow-binding inhibitors that react with the active site cysteine to irreversibly inhibit the enzyme [34]. …”

Section: Introductionmentioning

confidence: 99%

“…3-halo-dihydroisoxazoles (DHIs), sulfonium methyl ketones (incl. thioimidazolium derivatives), epoxides, 1,2,4-thiadiazoles, diazomethyl ketones, maleimides and acryloyl amides (Michael acceptors) have been developed as TG inhibitors [34], Through synthesis, screening and SAR, TG inhibitors with IC 50 < 100 nM and specificity for TG2 over fXIIIa have been developed [43,44]. …”

Section: Introductionmentioning

confidence: 99%

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Dihydroisoxazole inhibitors of Anopheles gambiae seminal transglutaminase AgTG3

Klöck

Schatz

et al. 2014

Malar J

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BackgroundCurrent vector-based malaria control strategies are threatened by the rise of biochemical and behavioural resistance in mosquitoes. Researching mosquito traits of immunity and fertility is required to find potential targets for new vector control strategies. The seminal transglutaminase AgTG3 coagulates male Anopheles gambiae seminal fluids, forming a ‘mating plug’ that is required for male reproductive success. Inhibitors of AgTG3 can be useful both as chemical probes of A. gambiae reproductive biology and may further the development of new chemosterilants for mosquito population control.MethodsA targeted library of 3-bromo-4,5-dihydroxoisoxazole inhibitors were synthesized and screened for inhibition of AgTG3 in a fluorescent, plate-based assay. Positive hits were tested for in vitro activity using cross-linking and mass spectrometry, and in vivo efficacy in laboratory mating assays.ResultsA targeted chemical library was screened for inhibition of AgTG3 in a fluorescent plate-based assay using its native substrate, plugin. Several inhibitors were identified with IC50 < 10 μM. Preliminary structure-activity relationships within the library support the stereo-specificity and preference for aromatic substituents in the chemical scaffold. Both inhibition of plugin cross-linking and covalent modification of the active site cysteine of AgTG3 were verified. Administration of an AgTG3 inhibitor to A. gambiae males by intrathoracic injection led to a 15% reduction in mating plug transfer in laboratory mating assays.ConclusionsA targeted screen has identified chemical inhibitors of A. gambiae transglutaminase 3 (AgTG3). The most potent inhibitors are known inhibitors of human transglutaminase 2, suggesting a common binding pose may exist within the active site of both enzymes. Future efforts to develop additional inhibitors will provide chemical tools to address important biological questions regarding the role of the A. gambiae mating plug. A second use for transglutaminase inhibitors exists for the study of haemolymph coagulation and immune responses to wound healing in insects.

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Transglutaminase 2 takes center stage as a cancer cell survival factor and therapy target

Eckert

2019

Molecular Carcinogenesis

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Transglutaminase 2 (TG2) has emerged as a key cancer cell survival factor that drives epithelial to mesenchymal transition, angiogenesis, metastasis, inflammation, drug resistance, cancer stem cell survival and stemness, and invasion and migration. TG2 can exist in a GTP‐bound signaling‐active conformation or in a transamidase‐active conformation. The GTP bound conformation of TG2 contributes to cell survival and the transamidase conformation can contribute to cell survival or death. We present evidence suggesting that TG2 has a role in human cancer, summarize what is known about the TG2 mechanism of action in a range of cancer types, and discuss TG2 as a cancer therapy target.

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Irreversible Inhibitors of Tissue Transglutaminase

Cited by 15 publications

References 71 publications

Irreversible 4-Aminopiperidine Transglutaminase 2 Inhibitors for Huntington's Disease

Irreversible 4-Aminopiperidine Transglutaminase 2 Inhibitors for Huntington's Disease

Dihydroisoxazole inhibitors of Anopheles gambiae seminal transglutaminase AgTG3

Transglutaminase 2 takes center stage as a cancer cell survival factor and therapy target

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