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1.
J Enzyme Inhib Med Chem ; 39(1): 2394895, 2024 Dec.
Article in English | MEDLINE | ID: mdl-39223706

ABSTRACT

The HECT E3 ubiquitin ligases 1 (WWP1) and 2 (WWP2) are responsible for the ubiquitin-mediated degradation of key tumour suppressor proteins and are dysregulated in various cancers and diseases. Here we expand their limited inhibitor space by identification of NSC-217913 displaying a WWP1 IC50 of 158.3 µM (95% CI = 128.7, 195.1 µM). A structure-activity relationship by synthesis approach aided by molecular docking led to compound 11 which displayed increased potency with an IC50 of 32.7 µM (95% CI = 24.6, 44.3 µM) for WWP1 and 269.2 µM (95% CI = 209.4, 347.9 µM) for WWP2. Molecular docking yielded active site-bound poses suggesting that the heterocyclic imidazo[4,5-b]pyrazine scaffold undertakes a π-stacking interaction with the phenolic group of tyrosine, and the ethyl ester enables strong ion-dipole interactions. Given the therapeutic potential of WWP1 and WWP2, we propose that compound 11 may provide a basis for future lead compound development.


Subject(s)
Dose-Response Relationship, Drug , Molecular Docking Simulation , Ubiquitin-Protein Ligases , Ubiquitin-Protein Ligases/antagonists & inhibitors , Ubiquitin-Protein Ligases/metabolism , Humans , Structure-Activity Relationship , Molecular Structure , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/chemical synthesis
2.
Angew Chem Weinheim Bergstr Ger ; 136(1): e202312104, 2024 Jan 02.
Article in English | MEDLINE | ID: mdl-38516647

ABSTRACT

S-adenosylmethionine-dependent methyltransferases are involved in countless biological processes, including signal transduction, epigenetics, natural product biosynthesis, and detoxification. Only a handful of carboxylate methyltransferases have evolved to participate in amide bond formation. In this report we show that enzyme-catalyzed F-methylation of carboxylate substrates produces F-methyl esters that readily react with N- or S-nucleophiles under physiological conditions. We demonstrate the applicability of this approach to the synthesis of small amides, hydroxamates, and thioesters, as well as to site-specific protein modification and native chemical ligation.

3.
Angew Chem Int Ed Engl ; 63(1): e202312104, 2024 Jan 02.
Article in English | MEDLINE | ID: mdl-37955592

ABSTRACT

S-adenosylmethionine-dependent methyltransferases are involved in countless biological processes, including signal transduction, epigenetics, natural product biosynthesis, and detoxification. Only a handful of carboxylate methyltransferases have evolved to participate in amide bond formation. In this report we show that enzyme-catalyzed F-methylation of carboxylate substrates produces F-methyl esters that readily react with N- or S-nucleophiles under physiological conditions. We demonstrate the applicability of this approach to the synthesis of small amides, hydroxamates, and thioesters, as well as to site-specific protein modification and native chemical ligation.


Subject(s)
Amides , Methyltransferases , Methyltransferases/metabolism , Methylation , Amides/chemistry , S-Adenosylmethionine/chemistry , Carboxylic Acids , Adenosine Triphosphate/metabolism , Biocatalysis
4.
Drug Discov Today ; 26(10): 2377-2383, 2021 10.
Article in English | MEDLINE | ID: mdl-33872800

ABSTRACT

Targeting protein-protein interactions (PPI) is a key focus in the development of new and emerging small-molecule therapeutics. Shallow interacting surfaces can render PPI targeting notoriously difficult. This leaves many therapeutically captivating targets 'undruggable'. Despite these challenges, there has been extraordinary progress circumventing this issue by hijacking the ubiquitin proteasome system (UPS) to target selected substrates for destruction using target-based degradation (TBD) strategies, including bifunctional molecules known as proteolysis-targeting chimeras (PROTACs). In this review, we discuss some of the most recent innovative concepts emerging from PROTAC research and related technologies.


Subject(s)
Drug Development/methods , Molecular Targeted Therapy , Proteins/metabolism , Drug Discovery/methods , Humans , Proteasome Endopeptidase Complex/metabolism , Proteolysis
5.
Chemistry ; 24(67): 17677-17680, 2018 Dec 03.
Article in English | MEDLINE | ID: mdl-30207403

ABSTRACT

We have screened small molecule libraries specifically for inhibitors that target WWP2, an E3 ubiquitin ligase associated with tumour outgrowth and spread. Selected hits demonstrated dose-dependent WWP2 inhibition, low micromolar IC50 values, and inhibition of PTEN substrate-specific ubiquitination. Binding to WWP2 was confirmed by ligand-based NMR spectroscopy. Furthermore, we used a combination of STD NMR, the recently developed DEEP-STD NMR approach, and docking calculations, to propose for the first time an NMR-validated 3D molecular model of a WWP2-inhibitor complex. These first generation WWP2 inhibitors provide a molecular framework for informing organic synthetic approaches to improve activity and selectivity.


Subject(s)
Enzyme Inhibitors/chemistry , Small Molecule Libraries/chemistry , Ubiquitin-Protein Ligases/antagonists & inhibitors , Binding Sites , Drug Discovery , Enzyme Inhibitors/metabolism , Humans , Inhibitory Concentration 50 , Ligands , Molecular Docking Simulation , Nuclear Magnetic Resonance, Biomolecular , PTEN Phosphohydrolase/metabolism , Protein Structure, Tertiary , Small Molecule Libraries/metabolism , Solubility , Ubiquitin-Protein Ligases/metabolism
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