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: 11.26). 02/2008; 47(20):3747-50. DOI: 10.1002/anie.200705795
Source: PubMed


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.

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    • "Both RGGT and Rab proteins have recently been implicated in numerous diseases including cancer, neurological disorders, bacterial and viral infections [13e15]. To date a few classes of RGGT inhibitors have been identified, including PC derivatives of BPs [4] [7] [11] [12], tripeptide analogues [16] [17], compounds derived from GGTase 1 inhibitors, with pentasubstituted pyrrolidine analogs [18], compounds Abbreviations: PC, phosphonocarboxylate; BP, bisphosphonate; RGGT, Rab geranylgeranyl transferase, Rab GGTase, GGTase 2; TAG tunnel, a tunnel adjacent to GGPP binding site in RGGT; FTase, farnesyl transferase; FPPS, farnesyl pyrophosphate synthase, farnesyl diphosphate synthase; GGTase 1, geranylgeranyl transferase 1; NFSI, N-fluoro-N-(phenylsulfonyl) benzenesulfonamide. * Corresponding author. "
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    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.
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    • "Therefore, RGGTase represents an intriguing new anti-osteoporosis target whereas compounds that inhibit geranylgeranylation by GGTase I may be more attractive in an anticancer setting. Recent identification of compounds that specifically inhibit GGTase I or RGGTase may provide further insights in these areas[247,248]. "
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