Identification of potent and selective TACE inhibitors via the S1 pocket

Chemical and Screening Sciences, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA.
Bioorganic & Medicinal Chemistry Letters (Impact Factor: 2.42). 02/2007; 17(1):34-9. DOI: 10.1016/j.bmcl.2006.10.004
Source: PubMed


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.

12 Reads
  • Source
    • "as PDB entries 1BKC [11], 1ZXC [4] and 2A8H [5] respectively. In addition PDB entry 2I47 [6], where the bound ligand contains a substituted isoxazole ring at the S 2 TACE sub-site, provides a suitable protein conformation for the docking of 2E. Finally, the protein conformation in 1ZXC also proved suitable for the docking of the sulfonamide 2B. "
    [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.
    Journal of molecular graphics & modelling 11/2010; 29(3):436-42. DOI:10.1016/j.jmgm.2010.08.006 · 1.72 Impact Factor
  • Q. Cao ·
    [Show abstract] [Hide abstract]
    ABSTRACT: A fundamental requirement for medium access control (MAC) protocols is to provide a unified bandwidth-on-demand platform to support an integrated mix of multimedia traffic with different QoS requirements, whilst stabilising contention-based access to achieve optimal throughput. Distributed queuing request update multiple access (DQRUMA) is an efficient bandwidth-on-demand fair-sharing protocol for wireless packet networks with multi-code CDMA. This paper therefore proposes a MAC protocol that maximises the channel throughput based on DQRUMA using a Bayesian feedback control model. Original contributions in the paper include: (1) an enhanced DQRUMA model by randomisation of packet transmissions, which is developed from single cell to cellular CDMA networks; and (2) a proposed control strategy which ensures that the system operates steadily at the optimal access throughput point. Numerical results and simulation verify the proposed protocol
    Vehicular Technology Conference, 1998. VTC 98. 48th IEEE; 06/1998
  • [Show abstract] [Hide abstract]
    ABSTRACT: Structure-based lead optimization approaches are increasingly playing a role in the drug-discovery process. Recent advances in 'high-throughput' molecular docking methods and examples of their successful use in lead optimization are reviewed. Measures of docking accuracy, scoring function comparisons, and consensus approaches are discussed. Differences in docking protocols typically used for lead optimization versus lead generation are highlighted; this section includes a discussion of the latest methods for the incorporation of protein flexibility. New approaches developed specifically for the design of combinatorial libraries as well as those designed or used for 'fragment' versus lead optimization are presented. Finally, potential future improvements to the technology are outlined.
    Current opinion in drug discovery & development 06/2007; 10(3):264-74. · 5.12 Impact Factor
Show more