A5089000739- Antibiotic Resistance in Bacteria
- Cancer-related gene regulation
- Biochemical and Molecular Research
- Epigenetics and DNA Methylation
- Tuberculosis Research and Epidemiology
- CRISPR and Genetic Engineering
- Pneumonia and Respiratory Infections
- Sirtuins and Resveratrol in Medicine
- RNA modifications and cancer
- Pneumocystis jirovecii pneumonia detection and treatment
- Chemical Synthesis and Analysis
- PI3K/AKT/mTOR signaling in cancer
- RNA Interference and Gene Delivery
- Peptidase Inhibition and Analysis
- Autophagy in Disease and Therapy
- PARP inhibition in cancer therapy
- Antibiotics Pharmacokinetics and Efficacy
- Click Chemistry and Applications
- Chronic Myeloid Leukemia Treatments
- Chronic Lymphocytic Leukemia Research
- Synthesis and Catalytic Reactions
- Alkaloids: synthesis and pharmacology
- Inhalation and Respiratory Drug Delivery
- Plant Disease Resistance and Genetics
- Marine Sponges and Natural Products
Leiden University
2019-2024
Utrecht University
2007-2020
Pharmo Institute
2014-2017
Cancer Genomics Centre
2014-2017
National Institute for Public Health and the Environment
2010
Combined Ophthalmic Research Rotterdam
1992
Nicotinamide N-methyltransferase (NNMT) catalyzes the methylation of nicotinamide to form N-methylnicotinamide. Overexpression NNMT is associated with a variety diseases, including number cancers and metabolic disorders, suggesting role for as potential therapeutic target. By structural modification lead inhibitor previously developed in our group, we prepared diverse library inhibitors probe different regions enzyme's active site. This investigation revealed that incorporation naphthalene...
Nicotinamide N-methyltransferase (NNMT) methylates nicotinamide (vitamin B3) to generate 1-methylnicotinamide (MNA). NNMT overexpression has been linked a variety of diseases, most prominently human cancers, indicating its potential as therapeutic target. The development small-molecule inhibitors gained interest in recent years, with the potent sharing structural features based on elements substrate and S-adenosyl-l-methionine (SAM) cofactor. We here report new bisubstrate that include...
Nicotinamide N-methyltransferase (NNMT) methylates nicotinamide to form 1-methylnicotinamide (MNA) using S-adenosyl-l-methionine (SAM) as the methyl donor. The complexity of role NNMT in healthy and disease states is slowly being elucidated provides an indication that may be interesting therapeutic target for a variety diseases including cancer, diabetes, obesity. Most inhibitors described date are structurally related one or both its substrates. In search diverse inhibitors, mRNA display...
Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer (IBC). Due to lack biomarkers able distinguish high- from low-risk cases, DCIS treated similar early IBC even though the minority untreated cases eventually become invasive. Here, we characterized 115 patient-derived mouse-intraductal (MIND) models reflecting full spectrum observed patients. Utilizing possibility follow natural progression combined with omics and imaging data, reveal multiple prognostic...
Nicotinamide N-methyltransferase (NNMT) is one of the most abundant small molecule methyltransferases in human body and primarily responsible for N-methylation nicotinamide (vitamin B3). Employing cofactor S-adenosyl-l-methionine, NNMT transfers a methyl group to pyridine nitrogen generate N-methylnicotinamide. Interestingly, also able N-methylate variety other pyridine-containing molecules, suggesting secondary role enzyme detoxification xenobiotics. A number recent studies have revealed...
PRMT inhibitors designed to simultaneously occupy both substrate binding sites display potent activity and surprising selectivity.
Nicotinamide N-methyltransferase (NNMT) is an enzyme that catalyses the methylation of nicotinamide to form N'-methylnicotinamide. Both NNMT and its methylated product have recently been linked a variety diseases, suggesting role for as therapeutic target beyond previously ascribed metabolic function in detoxification. We here describe systematic development inhibitors derived from structures substrates involved reaction. By covalently linking fragments diverse library bisubstrate-like...
A recently discovered bisubstrate inhibitor of Nicotinamide N-methyltransferase (NNMT) was found to be highly potent in biochemical assays with a single digit nanomolar IC50 value but lacking cellular activity. We, here, report prodrug strategy designed translate the observed inhibitory activity this into strong This relies on temporary protection amine and carboxylic acid moieties polar amino side chain present inhibitor. The modification range esters absence or presence trimethyl-lock...
Abstract Background Osteosarcoma (OS) is a primary bone malignancy that mostly affects young people, characterized by high metastatic potential, and marked chemoresistance responsible for disease relapse in most patients. Therefore, it necessary to identify novel molecules setup targeted strategies improve the clinical outcome. The enzyme nicotinamide N‐methyltransferase (NNMT) catalyses N‐methylation of other analogs, playing crucial role biotransformation drugs xenobiotics. NNMT...
Abstract Merkel cell carcinoma (MCC) is an aggressive skin cancer, with a propensity for early metastasis. Therefore, diagnosis and the identification of novel targets become fundamental. The enzyme nicotinamide N -methyltransferase (NNMT) catalyzes reaction -methylation other analogous compounds. Although NNMT overexpression was reported in many malignancies, significance its dysregulation cancer phenotype partly clarified. Several works demonstrated that promotes proliferation, migration,...
Significance The posttranslational methylation of arginine is a widespread epigenetic modification catalyzed by the family protein methyltransferases (PRMTs). Dysregulation PRMT expression implicated in pathogenesis many diseases including human cancers. An atomic-scale understanding catalytic mechanism crucial for both fundamental biological and pharmacological applications. Despite intense efforts, crystal structures complexes with long peptides full-length substrates have not been solved...
PRMT 2 is the less‐characterized member of protein arginine methyltransferase family in terms structure, activity, and cellular functions. a modular containing catalytic Ado‐Met‐binding domain unique Src homology 3 that binds proteins with proline‐rich motifs. involved variety processes has diverse roles transcriptional regulation through different mechanisms depending on its binding partners. been demonstrated to have weak activity histone H4 substrate, but optimal substrates not yet...
Ibrutinib is a targeted covalent inhibitor frequently used for the treatment of various lymphomas. In addition to oxidative metabolism, it metabolized through glutathione coupling. The quantitative insight into this kind metabolism scarce, and tools quantitation are lacking. non-oxidative could prove more prominent role when impaired. Also, in-vitro studies over-estimate effect CYP450-inhibition. To gain relatively unknown biotransformation pathway drug we have developed validated simple,...
The increasing prevalence of metallo-β-lactamase (MBL)-expressing bacteria presents a worrying trend in antibiotic resistance. MBLs rely on active site zinc ions for their hydrolytic activity and the pursuit MBL-inhibitors has therefore involved investigation chelators. To ensure that such chelators specifically target MBLs, series cephalosporin prodrugs two potent zinc-binders: dipicolinic acid (DPA) 8-thioquinoline (8-TQ) was prepared. Although both DPA 8-TQ bind free very tightly (Kd...
In an attempt to exploit the hydrolytic mechanism by which β-lactamases degrade cephalosporins, we designed and synthesized a series of novel cephalosporin prodrugs aimed at delivering thiol-based inhibitors metallo-β-lactamases (MBLs) in spatiotemporally controlled fashion. While enzymatic hydrolysis β-lactam ring was observed, it not accompanied inhibitor release. Nonetheless, prodrugs, especially thiomandelic acid conjugate (8), demonstrated potent inhibition IMP-type MBLs. addition, 8...
Metallo-β-lactamases (MBLs) are zinc-dependent bacterial enzymes that inactivate essentially all classes of β-lactam antibiotics including last-resort carbapenems. At present there no clinically approved MBL inhibitors, and in order to develop such agents it is essential understand their inhibitory mechanisms. Herein, we describe a comprehensive mechanistic study panel structurally distinct inhibitors reported both the scientific patent literature. Specifically, determined half-maximal...
This paper describes an optimized protocol for the efficient loading of resin-bound aminoethane sulfonyl azides by either Boc- or Fmoc-protected amino thioacids. The resulting N-acyl sulfonamide is a convenient linker use in Fmoc-based solid-phase peptide synthesis. Activation via microwave-assisted alkylation procedure and subsequent treatment with functionalized nucleophiles yields C-terminally modified peptides that can be applied chemoselective (bio)conjugation ligation reactions.
Aminocarboxylic acid analogues of aspergillomarasmine A (AMA) and ethylenediamine-<italic>N</italic>,<italic>N</italic>′-disuccinic (EDDS) were prepared<italic>via</italic>a robust chemoenzymatic approach. These compounds display potent inhibition the bacterial resistance enzyme NDM-1.
In the search for new inhibitors of bacterial metallo-β-lactamases (MBLs), a series commonly used small molecule carboxylic acid derivatives were evaluated their ability to inhibit New Delhi metallo-β-lactamase (NDM)-, Verona integron-encoded (VIM)-, and imipenemase (IMP)-type enzymes. Nitrilotriacetic (3) N-(phosphonomethyl)iminodiacetic (5) showed promising activity especially against NDM-1 VIM-2 with IC50 values in low-to-sub μM range. Binding assays using isothermal titration calorimetry...
Summary Ibrutinib is a first-in-class Bruton’s kinase inhibitor used in the treatment of multiple lymphomas. In addition to CYP3A4-mediated metabolism, glutathione conjugation can be observed. Subsequently, metabolism conjugates and finally their excretion feces urine occurs. These metabolites, however, reach substantial concentrations human subjects, especially when CYP3A4 inhibited. has unexplained nephrotoxicity high metabolite are also found kidneys Cyp3a knockout mice. Here, mechanism...
Targeting the PI3K-AKT-mTOR pathway is a promising therapeutic strategy for breast cancer treatment. However, low response rates and development of resistance to inhibitors remain major clinical challenges. Here, we show that MYC activation drives mTOR (mTORi) in cancer. Multiomic profiling mouse invasive lobular carcinoma (ILC) tumors revealed recurrent Myc amplifications acquired mTORi AZD8055. was associated with biological processes linked counteracted mTORi-induced translation...
Nicotinamide N-methyltransferase (NNMT) is responsible for the N-methylation of nicotinamide to 1-methylnicotinamide. Our recent studies have demonstrated that NNMT regulates cellular processes fundamental correct functioning and survival cell. It has been proposed may possess β-carboline (BC) activity, endogenously exogenously produced pyridine-containing compounds which, when N-methylated, are potent inhibitors Complex I a role in pathogenesis Parkinson's disease. We investigated ability...