Development of selective RabGGTase inhibitors and crystal structure of a RabGGTase-inhibitor complex
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.
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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    , tripeptide analogues  , compounds derived from GGTase 1 inhibitors, with pentasubstituted pyrrolidine analogs , 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. "
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
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ABSTRACT: Lipidation of proteins is an important mechanism to regulate protein trafficking and activity in cell and tissues. The targeting of proteins to membranes by lipidation plays key roles in many physiological processes and when not regulated properly can lead to cancer and neurological disorders. Dissecting the precise roles of protein lipidation in physiology and disease is a major challenge. Recent advances in chemical biology have now enabled the semisynthesis of lipidated proteins for fundamental biochemical and cellular studies. In addition, new chemical reporters of protein lipidation have improved the detection and enabled the proteomic analysis of lipidated proteins. The expanding efforts in chemical biology are therefore providing new tools to dissect the mechanisms and functions of protein lipidation as well as develop therapeutics targeted at protein lipidation pathways in disease.Current opinion in chemical biology 09/2009; 13(4):382-91. DOI:10.1016/j.cbpa.2009.07.010 · 7.65 Impact Factor
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ABSTRACT: Rab geranylgeranyl transferase (RabGGTase) catalyzes the attachment of geranylgeranyl isoprenoids to Rab guanine triphosphatases, which are key regulators in vesicular transport. Because geranylgeranylation is required for proper function and overexpression of Rabs has been observed in various cancers, RabGGTase may be a target for novel therapeutics. The development of selective inhibitors is, however, difficult because two related enzymes involved in other cellular processes exist in eukaryotes and because RabGGTase recognizes protein substrates indirectly, resulting in relaxed specificity. We report the synthesis of a peptidic library based on the farnesyl transferase inhibitor pepticinnamin E. Of 469 compounds investigated, several were identified as selective for RabGGTase with low micromolar IC(50) values. The compounds were not generally cytotoxic and inhibited Rab isoprenylation in COS-7 cells. Crystal structure analysis revealed that selective inhibitors interact with a tunnel unique to RabGGTase, implying that this structural motif is an attractive target for improved RabGGTase inhibitors.Journal of Medicinal Chemistry 11/2009; 52(24):8025-37. DOI:10.1021/jm901117d · 5.48 Impact Factor