Article

Development of selective RabGGTase inhibitors and crystal structure of a RabGGTase-inhibitor complex

Max-Planck-Institut für molekulare Physiologie, Abt. Physikalische Biochemie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
Angewandte Chemie International Edition (Impact Factor: 11.34). 02/2008; 47(20):3747-50. DOI: 10.1002/anie.200705795
Source: PubMed

ABSTRACT Ende des Transfers: Ausgehend von der Struktur von Pepticinnamin E wurden Inhibitoren der Rab-Geranylgeranyltransferase (RabGGTase) mit zellulärer Aktivität entwickelt. Die erste Kristallstruktur des Enzyms im Komplex mit einem Inhibitor wird vorgestellt (siehe die Struktur des Inhibitors und seine Positionierung im aktiven Zentrum des Enzyms). Die Ergebnisse sind wichtig für chemisch-biologische Studien zur Prenylierung und zum vesikulären Transport und zur Beteiligung von RabGGTase an der Entstehung von Krankheiten.

0 Bookmarks
 · 
117 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Members of the Ras superfamily of small GTPases are frequently mutated in cancer. Therefore, inhibitors have been developed to address the acitivity of these GTPases by inhibiting their prenylating enzymes FTase, GGTase I, and RabGGTase. In contrast to FTase and GGTase I, only a handful of RabGGTase inhibitors have been developed. The most active RabGGTase inhibitor known until recently was an FTase inhibitor which hit RabGGTase as an off-target. We recently reported our efforts to tune the selectivity of these inhibitors toward RabGGTase. Here we describe an extended set of selective inhibitors. The requirements for selective RabGGTase inhibitors are described in detail, guided by multiple crystal structures. In order to relate in vitro and cellular activity, a high-throughput assay system to detect the attachment of [(3)H]geranylgeranyl groups to Rab was used. Selective RabGGTase inhibition allows the establishment of novel drug discovery programs aimed at the development of anticancer therapeutics.
    Journal of Medicinal Chemistry 09/2012; 55(19):8330-40. DOI:10.1021/jm300624s · 5.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Phosphonocarboxylate (PC) analogs of the anti-osteoporotic drugs, bisphosphonates, represent the first class of selective inhibitors of Rab geranylgeranyl transferase (RabGGTase, RGGT), an enzyme implicated in several diseases including ovarian, breast and skin cancer. Here we present the synthesis and biological characterization of an extended set of this class of compounds, including lipophilic derivatives of the known RGGT inhibitors. From this new panel of PCs, we have identified an inhibitor of RGGT that is of similar potency as the most active published phosphonocarboxylate, but of higher selectivity towards prenyl pyrophosphate synthases. New insights into structural requirements are also presented, showing that only PC analogs of the most potent 3rd generation bisphosphonates inhibit RGGT. In addition, the first phosphonocarboxylate-derived GGPPS weak inhibitor is reported.
    European Journal of Medicinal Chemistry 06/2014; 84C:77-89. DOI:10.1016/j.ejmech.2014.06.062 · 3.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The posttranslational modification of protein prenylation is a covalent lipid modification on the C-terminus of substrate proteins that serves to enhance membrane affinity. Oncogenic proteins such as Ras have this modification and significant effort has been placed into developing inhibitors of the prenyltransferase enzymes for clinical therapy. In addition to cancer therapy, prenyltransferase inhibitors have begun to find important therapeutic uses in other diseases, including progeria, hepatitis C and D, parasitic infections, and other maladies. This review will trace the evolution of prenyltransferase inhibitors from their initial use as cancer therapeutics to their expanded applications for other diseases.
    Medicinal Chemistry Communication 02/2013; 4(3):476-492. DOI:10.1039/C2MD20299A · 2.63 Impact Factor