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.

14 Reads
  • Source
    • "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. "
    [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 · 3.45 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Inhibitors of isoprenoid biosynthesis are widely used to treat human disease including statins and nitrogenous bisphosphonates. Due to the importance of core human isoprenoid biosynthesis for diverse cellular processes related to cancer cell growth and metastasis, inhibition of this pathway may produce beneficial anticancer consequences. For example, ras oncogenes are well known; ras proteins are overexpressed in many human cancers, and these proteins must be isoprenylated to function. The rho proteins are important for regulating cell motility, and also must be isoprenylated. This has drawn significant attention to inhibitors of protein prenyl transferases. In addition to the reactions that are targeted in current clinical applications, there are other enzymes that have not been studied as extensively. Inhibition of these enzymes, from mevalonate kinase to geranylgeranyl diphosphate synthase, could be attractive as a single agent therapy or in combination with current agents for treatment of cancers in which isoprenylated proteins have been implicated. While detailed in vivo data for many of these putative targets is lacking, there have been several breakthroughs in recent years that could facilitate further studies. In particular, compounds that specifically inhibit some of the downstream isoprenoid biosynthesis enzymes have been developed and their effects in cancer models are emerging. This review will discuss current knowledge of these lesser known isoprenoid pathway enzymes, identify trends in the development of their small molecule inhibitors, and describe the applications and effects of these compounds in cancer models.
    Anti-cancer agents in medicinal chemistry 07/2009; 9(5):526-42. DOI:10.2174/187152009788451860 · 2.47 Impact Factor
  • [Show abstract] [Hide abstract]
    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 · 6.81 Impact Factor
Show more