Identification of potent and selective TACE inhibitors via the S1 pocket

ArticleinBioorganic & Medicinal Chemistry Letters 17(1):34-9 · February 2007with17 Reads
DOI: 10.1016/j.bmcl.2006.10.004 · Source: PubMed
Abstract
By focusing on the P1 portion of the piperidine beta-sulfone ligands we identified a motif that induces selectivity and resulted in a series of TACE inhibitors that demonstrated excellent in vitro potency against isolated TACE enzyme and excellent selectivity over MMPs 1, 2, 9, 13, and 14.
    • "These groups are collagenases (MMP-1, MMP-8 and MMP-13), gelatinases (MMP-9), stromelysins (MMP-3), matrilysins (MMP-7) and membrane-type MMPs (MT-MMPs) (MMP-16), respectively. The six MMPs were selected based on a literature survey where TACE inhibitors also showed MMP inhibitory activity [34,35]. Various MMPs such as MMP1 (PDB code 1HFC), MMP3 (PDB code 1HY7), MMP7 (PDB code 2Y6D), MMP8 (PDB code 1I76), MMP9 (PDB code 2OVX), MMP13 (PDB code 3ZXH) and MMP16 (PDB code 1RM8) were considered for the study. "
    [Show abstract] [Hide abstract] ABSTRACT: Tumor necrosis factor-α (TNF-α) converting enzyme (TACE) has been considered one of the principal therapeutic targets for the treatment of TNF-dependent pathologies. Several TACE inhibitors have been reported, but none of them has been successfully passed to phase II clinical trials. In the present work, we attempted to design highly selective new non-hydroxamate sulfonamide TACE inhibitors. The docking study was performed on one of the crystal structures of TACE, selected based on its resolution and R value, to tackle the flexibility issue of the active site. The results allowed us to distinguish the analogues with a higher binding affinity toward the active site of TACE and to identify the substituent of analogues needed for binding with the surrounding site of the enzyme. Finally the analogues were docked on crystal structures of six different matrix metalloproteinases (MMPs) for a selectivity study of TACE over MMPs. Some of these analogues were synthesized and subjected to preliminary testing for in vivo anti-inflammatory activity and TACE inhibitory activity.
    Full-text · Article · Nov 2015
    • "Finally, the conformations are further refined via a Monte Carlo sampling of pose conformation. For the present study, X-ray crystal structure of TACE with resolution of 1.9 Å was taken from PDB (ID: 2i47) [34]. The performance of docking method was evaluated by re-docking crystal ligand and correlating the binding pose as well as hydrogen bonding interactions of redocked crystal ligand with original crystal ligand. "
    Full-text · Article · Jan 2011
    • "This is reflected in a much weaker, both calculated and observed, micromolar inhibition of ADAM10 by TAPI-2. While inhibitor 2E exhibits much greater selectivity for TACE over MMP-1 and MMP-9, and to a lesser but still significant extent over MMP-2 and MMP-13, TMI-1 displays markedly less selectivity for TACE over MMP-1 and MMP-9, and no selectivity at all over MMP-13 [6]. Surprisingly, given their similar phylogenetic profile [8], TMI-1 remains moderately selective for TACE over ADAM10, as shown by the values for K i inTable 1. "
    [Show abstract] [Hide abstract] ABSTRACT: The matrix metalloproteinase family has been a pharmaceutical target for most of the last three decades, but success has been hampered by unwanted side effects caused by lack of selectivity, poor oral bioavailability and decreased potency in vivo. The surface-expressed metalloproteinases ADAM10 and ADAM17, the latter also referred to as TACE, play important roles in various physiological processes, especially involving tissue repair and development. Because of its role in the release of the cytokine TNF-α TACE has been a key target for pharmaceutical intervention in the treatment of rheumatoid arthritis. An extensive body of structural activity data has been developed for a series of small molecule inhibitors of TACE based on a sulfonamide scaffold containing key acetylenic substituents. We have undertaken an extensive molecular modeling study of select members of this ligand group to better understand the structural nuances involved in the development of ever more potent TACE inhibitors, and identify those elements of structure-based design that would enhance the selectivity of such inhibitors for TACE over ADAM10. Results include the identification of a flexible loop, comparable to that found in other MMPs that plays a subtle, yet significant, role in determining inhibitor potency.
    Full-text · Article · Nov 2010
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