18 research outputs found

    Paving the way to targeting HECT ubiquitin ligases

    No full text

    Tetracycline analogues with a selective inhibitory effect on HIF-1α

    No full text
    As part of a programme to discover novel transcription factor inhibitors, a 40-membered library of tetracycline analogues was screened to identify potential HIF-1 inhibitors. Two novel analogues (5b and 5c) with significant HIF-1 modulation properties were identified. These molecules possess good cellular penetration properties, and provide significant down-regulation of VEGF in U251 cells

    Molecular Dynamics Studies of the STAT3 Homodimer:DNA Complex: Relationships between STAT3 Mutations and Protein–DNA Recognition

    No full text
    Signal Transducers and Activators of Transcription (STAT) proteins are a group of latent cytoplasmic transcription factors involved in cytokine signaling. STAT3 is a member of the STAT family and is expressed at elevated levels in a large number of diverse human cancers and is now a validated target for anticancer drug discovery.. Understanding the dynamics of the STAT3 dimer interface, accounting for both protein–DNA and protein–protein interactions, with respect to the dynamics of the latent unphosphorylated STAT3 monomer, is important for designing potential small-molecule inhibitors of the activated dimer. Molecular dynamics (MD) simulations have been used to study the activated STAT3 homodimer:DNA complex and the latent unphosphorylated STAT3 monomer in an explicit water environment. Analysis of the data obtained from MD simulations over a 50 ns time frame has suggested how the transcription factor interacts with DNA, the nature of the conformational changes, and ways in which function may be affected. Examination of the dimer interface, focusing on the protein–DNA interactions, including involvement of water molecules, has revealed the key residues contributing to the recognition events involved in STAT3 protein–DNA interactions. This has shown that the majority of mutations in the DNA-binding domain are found at the protein–DNA interface. These mutations have been mapped in detail and related to specific protein–DNA contacts. Their structural stability is described, together with an analysis of the model as a starting-point for the discovery of novel small-molecule STAT3 inhibitors

    Investigation of the protein alkylation sites of the STAT3:STAT3 inhibitor Stattic by mass spectrometry

    No full text
    STAT3 (Signal Transducer and Activator of Transcription factor 3) is constitutively active in a wide range of human tumours. Stattic is one of the first non-peptidic small molecules reported to inhibit formation of the STAT3:STAT3 protein dimer complex. A mass spectrometry method has been developed to investigate the binding of Stattic to the un-phosphorylated STAT3ÎČtc (U-STAT3) protein. Alkylation of four cysteine residues has been observed with possible reaction at a fifth which could account for the mechanism of action.Peer reviewe
    corecore