Inhibitors of Protein Geranylgeranyltransferase I and Rab Geranylgeranyltransferase Identified from a Library of Allenoate-derived Compounds

Protein geranylgeranylation is critical for the function of a number of proteins such as RhoA, Rac, and Rab. Protein geranylgeranyltransferase I (GGTase-I) and Rab geranylgeranyltransferase (RabGGTase) catalyze these modifications. In this work, we first describe the identification and characterization of small molecule inhibitors of GGTase-I (GGTI) with two novel scaffolds from a library consisting of allenoate-derived compounds. These compounds exhibit specific inhibition of GGTase-I and act by competing with a substrate protein. Derivatization of a carboxylic acid emanating from the core ring of one of the GGTI compounds dramatically improves their cellular activity. The improved GGTI compounds inhibit proliferation of a variety of human cancer cell lines and cause G1 cell cycle arrest and induction of p21CIP1/WAF1. We also report the identification of novel small molecule inhibitors of RabGGTase. These compounds were identified first by screening our GGTI compounds for those that also exhibited RabGGTase inhibition. This led to the discovery of a common structural feature for RabGGTase inhibitors: the presence of a characteristic six-atom aliphatic tail attached to the penta-substituted pyrrolidine core. Further screening led to the identification of compounds with preferential inhibition of RabGGTase. These compounds inhibit RabGGTase activity by competing with the substrate protein. These novel compounds may provide valuable reagents to study protein geranylgeranylation. Protein geranylgeranylation is critical for the function of a number of proteins such as RhoA, Rac, and Rab. Protein geranylgeranyltransferase I (GGTase-I) and Rab geranylgeranyltransferase (RabGGTase) catalyze these modifications. In this work, we first describe the identification and characterization of small molecule inhibitors of GGTase-I (GGTI) with two novel scaffolds from a library consisting of allenoate-derived compounds. These compounds exhibit specific inhibition of GGTase-I and act by competing with a substrate protein. Derivatization of a carboxylic acid emanating from the core ring of one of the GGTI compounds dramatically improves their cellular activity. The improved GGTI compounds inhibit proliferation of a variety of human cancer cell lines and cause G1 cell cycle arrest and induction of p21CIP1/WAF1. We also report the identification of novel small molecule inhibitors of RabGGTase. These compounds were identified first by screening our GGTI compounds for those that also exhibited RabGGTase inhibition. This led to the discovery of a common structural feature for RabGGTase inhibitors: the presence of a characteristic six-atom aliphatic tail attached to the penta-substituted pyrrolidine core. Further screening led to the identification of compounds with preferential inhibition of RabGGTase. These compounds inhibit RabGGTase activity by competing with the substrate protein. These novel compounds may provide valuable reagents to study protein geranylgeranylation. Protein prenylation is a post-translational modification of proteins involving the addition of isoprenoids (1Tamanoi F. Sigman D.S. The Enzymes. 21. Academic Press, San Diego2001Google Scholar, 2Zhang F.L. Casey P.J. Annu. Rev. Biochem. 1996; 65: 241-270Crossref PubMed Scopus (1738) Google Scholar, 3Glomset J.A. Gelb M.H. Farnsworth C.C. Trends Biochem. Sci. 1990; 15: 139-142Abstract Full Text PDF PubMed Scopus (392) Google Scholar, 4Gelb M.H. Brunsveld L. Hrycyna C.A. Michaelis S. Tamanoi F. Van Voorhis W.C. Waldmann H. Nat. Chem. Biol. 2006; 10: 518-528Crossref Scopus (157) Google Scholar, 5Cox A.D. Der C.J. Curr. Opin. Cell Biol. 1992; 4: 1008-1016Crossref PubMed Scopus (201) Google Scholar). Specifically, protein farnesylation involves the addition of a C15 farnesyl group to proteins ending with the C-terminal CAAX motif (where C is cysteine; A is an aliphatic amino acid; and X is usually serine, methionine, glutamine, cysteine, or alanine). Farnesylated proteins include Ras proteins, Rheb proteins, nuclear lamins, and Hdj2. Protein geranylgeranylation involves the addition of a longer isoprenoid, C20 geranylgeranyl group. Two different types of geranylgeranylation have been reported. Rho family proteins such as RhoA, Cdc42, and Rac as well as the γ-subunit of heterotrimeric G-proteins are geranylgeranylated at a cysteine within the CAAL motif (similar to the CAAX motif, but the C-terminal amino acid is leucine or phenylalanine) at their C termini. Rab proteins involved in protein transport across the secretory and endocytosis pathways are also geranylgeranylated. These proteins usually end with CC (two cysteines) or CXC at the C termini, and both cysteines are geranylgeranylated. Recent studies highlight the physiological significance of protein geranylgeranylation. Knock-out mice specific for the β-subunit of geranylgeranyltransferase I (GGTase-I) 2The abbreviations used are:GGTase-Igeranylgeranyltransferase IRabGGTaseRab geranylgeranyltransferaseREPRab escort proteinGGTIgeranylgeranyltransferase I inhibitorFBSfetal bovine serumGGPPgeranylgeranyl diphosphateFTasefarnesyltransferaseCHAPS3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acidRabGGTIRab geranylgeranyltransferase inhibitor. have been established (6Sjogren A.K. Andersson K.M. Liu M. Cutts B.A. Karlsson C. Wahlstrom A.M. Dalin M. Weinbaum C. Casey P.J. Tarkowski A. Swolin B. Young S.G. Bergo M.O. J. Clin. Investig. 2007; 117: 1294-1304Crossref PubMed Scopus (93) Google Scholar). Characterization of GGTase-I-deficient cells showed proliferation inhibition and accumulation of p21CIP1/WAF1, pointing to the significance of GGTase-I in cell proliferation and cell cycle progression (6Sjogren A.K. Andersson K.M. Liu M. Cutts B.A. Karlsson C. Wahlstrom A.M. Dalin M. Weinbaum C. Casey P.J. Tarkowski A. Swolin B. Young S.G. Bergo M.O. J. Clin. Investig. 2007; 117: 1294-1304Crossref PubMed Scopus (93) Google Scholar). GGTase-I deficiency reduced oncogenic K-ras-induced lung tumor formation in mice, pointing to the significance of inhibiting GGTase-I to block tumor formation (6Sjogren A.K. Andersson K.M. Liu M. Cutts B.A. Karlsson C. Wahlstrom A.M. Dalin M. Weinbaum C. Casey P.J. Tarkowski A. Swolin B. Young S.G. Bergo M.O. J. Clin. Investig. 2007; 117: 1294-1304Crossref PubMed Scopus (93) Google Scholar). Recent studies also showed that a number of geranylgeranylated proteins play important roles in tumorigenesis and metastasis. In addition to RhoA and Cdc42 proteins, RalA protein was recently found to be activated downstream of Ras in most pancreatic cancer cells harboring oncogenic K-ras mutation (7Lim K.H. Baines A.T. Fiordalisi J.J. Shipitsin M. Feig L.A. Cox A.D. Der C.J. Counter C.M. Cancer Cell. 2005; 6: 533-545Abstract Full Text Full Text PDF Scopus (293) Google Scholar). RalB plays critical roles in the survival pathway (8Chien Y. White M.A. EMBO Rep. 2003; 4: 800-806Crossref PubMed Scopus (161) Google Scholar). RhoC is overexpressed in metastatic cancer, and RhoC knock-out mice exhibit defects in metastasis (9Clark E.A. Golub T.R. Lander E.S. Hynes R.O. Nature. 2000; 406: 532-535Crossref PubMed Scopus (1308) Google Scholar, 10Hakem A. Sanchez-Sweatman O. You-Ten A. Duncan G. Wakeham A. Khokha R. Mak T.W. Genes Dev. 2005; 19: 1974-1979Crossref PubMed Scopus (257) Google Scholar). Overexpression of Rab25 in breast and ovarian cancer cells has been reported, and this mutation is a determinant for the aggressiveness of these cancers (11Cheng K.W. Lahad J.P. Kuo W.L. Lapuk A. Yamada K. Auersperg N. Liu J. Smith-McCune K. Lu K.H. Fishman D. Gray J.W. Mills G.B. Nat. Med. 2004; 10: 1251-1256Crossref PubMed Scopus (421) Google Scholar, 12Cheng K.W. Lahad J.P. Gray J.W. Mills G.B. Cancer Res. 2005; 65: 2516-2519Crossref PubMed Scopus (178) Google Scholar). Rab25 is also up-regulated in prostate cancer and transitional cell bladder cancer (11Cheng K.W. Lahad J.P. Kuo W.L. Lapuk A. Yamada K. Auersperg N. Liu J. Smith-McCune K. Lu K.H. Fishman D. Gray J.W. Mills G.B. Nat. Med. 2004; 10: 1251-1256Crossref PubMed Scopus (421) Google Scholar). Overexpression of other Rab proteins such as Rab5a and Rab7 in cancer has been reported (13Croizet-Berger K. Daumerie C. Couvreur M. Courtoy P.J. van den Hove M.F. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 8277-8282Crossref PubMed Scopus (75) Google Scholar, 14He H. Dai F. Yu L. She X. Zhao Y. Jiang J. Chen X. Zhao S. Gene Expr. 2002; 10: 231-242Crossref PubMed Scopus (111) Google Scholar). geranylgeranyltransferase I Rab geranylgeranyltransferase Rab escort protein geranylgeranyltransferase I inhibitor fetal bovine serum geranylgeranyl diphosphate farnesyltransferase 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid Rab geranylgeranyltransferase inhibitor. Protein geranylgeranylation is catalyzed by two types of enzymes. GGTase-I catalyzes monogeranylgeranylation of proteins such as Rho, Rac, and Cdc42. This enzyme is a heterodimer consisting of α- and β-subunits (15Taylor J.S. Reid T.S. Terry K.L. Casey P.J. Beese L.S. EMBO J. 2003; 22: 5963-5974Crossref PubMed Scopus (109) Google Scholar). Rab geranylgeranyltransferase (RabGGTase or GGTase-II) catalyzes digeranylgeranylation of Rab proteins (16Leung K.F. Baron R. Seabra M.C. J. Lipid Res. 2006; 47: 467-475Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar, 17Zhang H. Seabra M.C. Deisenhofer J. Structure (Lond.). 2000; 8: 241-251Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar). This enzyme also contains α- and β-subunits, but contains an additional subunit, the Rab escort protein (REP) (16Leung K.F. Baron R. Seabra M.C. J. Lipid Res. 2006; 47: 467-475Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar, 18Pylypenko O. Rak A. Reents R. Niculae A. Sidorovitch V. Cioaca M.D. Bessolitsyna E. Thoma N.H. Waldmann H. Schlichting I. Goody R.S. Alexandrov K. Mol. Cell. 2003; 11: 483-494Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar). The REP subunit binds to the substrate Rab protein (19Rak A. Pylypenko O. Niculae A. Pyatkov K. Goody R.S. Alexandrov K. Cell. 2004; 117: 749-760Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). The α- and β-subunits share homology with corresponding subunits of GGTase-I. Small molecule inhibitors of GGTases (GGTIs) provide novel reagents to study geranylgeranylation. Development of peptidomimetic GGTI compounds derived from the CAAL peptide was pioneered by Sebti and co-workers (20Sebti S.M. Adjei A.A. Semin. Oncol. 2004; 31: 28-39Crossref PubMed Scopus (101) Google Scholar, 21Lerner E.C. Qian Y. Hamilton A.D. Sebti S.M. J. Biol. Chem. 1995; 270: 26770-26773Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar, 22Vasudevan A. Qian Y. Vogt A. Blaskovich M.A. Ohkanda J. Sebti S.M. Hamilton A.D. J. Med. Chem. 1999; 42: 1333-1340Crossref PubMed Scopus (78) Google Scholar, 23Sun J. Qian Y. Hamilton A.D. Sebti S.M. Oncogene. 1998; 16: 1467-1473Crossref PubMed Scopus (219) Google Scholar, 24Sun J. Ohkanda J. Coppola D. Yin H. Kothare M. Busciglio B. Hamilton A.D. Sebti S.M. Cancer Res. 2003; 63: 8922-8929PubMed Google Scholar); compounds (GGTI-298, GGTI-2154, etc.) exhibit cellular effects, including cell cycle arrest and apoptosis induction, and inhibit tumor growth in mice. However, development of non-peptidomimetic inhibitors lagged behind. Recently, the first non-peptidomimetic compound, GGTI-DU40, was reported (25Peterson Y.K. Kelly P. Weinbaum C.A. Casey P.J. J. Biol. Chem. 2006; 281: 12445-12450Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar). As for RabGGTase inhibitors, no effective inhibitors have been identified so far (26El Oualid F. Cohen L.H. van der Marel G.A. Overhand M. Curr. Med. Chem. 2006; 13: 2385-2427Crossref PubMed Scopus (29) Google Scholar). 2-Hydroxy-2-phosphono-3-(3-pyridinyl)-propanoic acid has been shown to inhibit geranylgeranylation of Rab proteins; however, a high concentration (mm) of compound was used to achieve inhibition (27Coxon F.P. Helfrich M.H. Larijani B. M. D. A.D. M.A. Seabra M.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). development of compounds that inhibit GGTase-I or RabGGTase is of as provide novel reagents to our of protein geranylgeranylation. In this we first report the identification and characterization of novel inhibitors of GGTase-I that were identified from a compound library that we S. M. P. Tamanoi F. O. J. Chem. 2007; PubMed Scopus Google Scholar). A specific modification that improves their cellular activity has been we report the identification and characterization of novel compounds with preferential inhibition of RabGGTase. These compounds have a that is with GGTI but an structural Cell and Cell cells were in with fetal bovine serum and cells were in with and cells were in with and cells were in with and diphosphate and diphosphate were from was by was from The used are enzymes. farnesyltransferase and Rab7 were from were from The allenoate-derived compound including and were as S. M. P. Tamanoi F. O. J. Chem. 2007; PubMed Scopus Google Scholar). for the of and compounds and be D. G. M. L. F. and O. in In and were by the of or substrate or GGTase-I was used to diphosphate or and for and RhoA for in and were at the The concentration was for were for at The was a and with by and The was a in the concentration was of GGTase-I and RhoA, and were for of GGTase-I and were used the of RhoA was RabGGTase the the in Rab7 or and were for at and the were as for the GGTase-I and were San of in of protein geranylgeranylation was by the accumulation of the of cells were in and or inhibitors were was for The cells were and in and inhibitor cell of cells were a to and with the of or was used as a of Rab geranylgeranylation in cells was as L. M. Biochem. 1995; PubMed Scopus Google Scholar). cell were to and by with or were as by J.S. Seabra M.C. Mol. Biol. 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G. and O. X. J. O. 2005; PubMed Scopus Google and X. A. O. 2005; PubMed Scopus (169) Google Scholar). The identification of GGTI compounds was first by screening a library an in with RhoA protein as a that showed activity were by This to two types of novel one group a ring as core and the other group a ring as core the and of compounds from with a of group. Two compounds with the in and were As and inhibit GGTase-I with of and The of GGTase-I inhibition by and was by their to inhibit two and RabGGTase. inhibition of activity by these compounds was the concentration was to showed inhibition of RabGGTase at showed inhibition of RabGGTase to with the of the inhibition of GGTase-I is shown in the derived from the of derived from the of the substrate protein These that and are inhibitors with to the substrate protein and inhibitors with to and for of the protein substrate but the substrate of GGTase-I. of and were for and of the of GGTI by of found that a group of the ring of improved cellular activity. This is shown in we a of compounds with different the group. The of these compounds to inhibit proliferation of cells was and their are The compound a carboxylic acid exhibited inhibition of proliferation of cells with an of the acid to an cellular However, of this led to in of with an group in of cellular Two and showed with of and in inhibiting proliferation of of the activity of and in the pancreatic cancer cell and cells is shown in The improved of these compounds to inhibit cell proliferation with their to inhibit protein geranylgeranylation the this and are shown in In this inhibition of protein geranylgeranylation was an that with or led to the of the in a that the of the was at with was with a in the of to inhibit protein geranylgeranylation. In to inhibit protein This was the protein inhibitor the of protein no such was with or GGTI compound, inhibit geranylgeranylation of as a that of was with RabGGTase inhibitors and with exhibited improved to inhibit geranylgeranylation in to inhibit the GGTase-I enzyme was that of as the for enzyme inhibition was inhibition of or RabGGTase activity by the compound was the concentration was to GGTI of Cancer Cell and G1 Cell shown in inhibition of proliferation of a variety of human cancer cell lines was these GGTI compounds inhibit a of human cancer cell The inhibition of proliferation by GGTI to be to the inhibition of cell cycle As shown in of the breast cancer cell with or inhibition of This was with a of G1 the of cells and G1 was with a cell two pancreatic cancer cell and and breast cancer cell of the of GGTI cell cycle progression is the inhibition of RhoA, of the inhibitor p21CIP1/WAF1. our GGTI compound the M.A. N.H. Oncogene. 15: PubMed Scopus Google was with cells were used to the of to induction of activity in a of of GGTase-I and characterization of our library of allenoate-derived compounds novel compounds that have the to inhibit RabGGTase. The identification of these novel compounds was by the that exhibited a inhibition of RabGGTase at This to that these have the to act RabGGTase. this were the we that be to a of GGTI compounds that inhibit RabGGTase. this we our library of compounds to the compounds that exhibited GGTase-I and to we compounds that also RabGGTase. The was RabGGTase as compounds that exhibited GGTase-I inhibition inhibition at we found that compounds also exhibited the to inhibit RabGGTase inhibition at the most compounds and that exhibited inhibition of both GGTase-I and RabGGTase in the the other these compounds inhibit at and of their led to a feature that is common to these have a characteristic aliphatic tail attached to the penta-substituted pyrrolidine core RabGGTase inhibitor of of the feature is as this feature may be used to activity. We first our library and identified compounds that have this We these compounds by RabGGTase This in the identification of compounds that exhibited preferential inhibition of RabGGTase inhibition of GGTase-I at and inhibition of RabGGTase at the and for the most preferential and of these compounds an at of the pyrrolidine we found and in the group of preferential As shown in and these compounds RabGGTase with of the inhibition of GGTase-I inhibition of was with these compounds at of Rab geranylgeranylation in cells was protein. In this we the of proteins one of the preferential the of a protein that an L. M. Biochem. 1995; PubMed Scopus Google Scholar). the other cause a of and the of that inhibit or GGTase-I. We also the of proteins with in an of protein in the with the was to our compounds with the substrate protein. RabGGTase of a core the α- and β-subunits, and the REP these subunits were first in the presence of a concentration of the concentration of substrate was and the of inhibition by was As shown in the compound RabGGTase activity with to the substrate protein the other the concentration of the inhibition by that are inhibitors with to A of was from these In this work, we first reported the identification of novel small molecule inhibitors of GGTase-I from the library of allenoate-derived compounds. Two novel scaffolds were compounds are non-peptidomimetic inhibitors that with the substrate protein. inhibition of protein geranylgeranylation but protein farnesylation was established with the as well as with non-peptidomimetic GGTI compounds have been reported (25Peterson Y.K. Kelly P. Weinbaum C.A. Casey P.J. J. Biol. Chem. 2006; 281: 12445-12450Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar); however, was used to cellular activity with compounds an important addition to the of GGTI compounds. We found that of the group of the ring of our compound, in a in cellular In the group to the corresponding by with was the other the carboxylic acid the to to a in These that the was to the of the but that the an additional The of the cellular activity of our GGTI compound with an in the to inhibit protein as by the of protein. the other the modification the of these compounds to inhibit GGTase-I the of cellular activity may cellular or of the GGTI compounds exhibit inhibition of proliferation of human cancer cell including pancreatic cancer, and breast cancer cell of the of GGTI is that this of inhibitors cell cycle arrest at the G1 A. J. Qian Y. Hamilton A.D. Sebti S.M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus (169) Google Scholar, J. Qian Y. Chen J. Hamilton A.D. Sebti S.M. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). inhibitors exhibited G1 arrest with the human cancer cell lines and In G1 arrest was with a breast cancer cell In our GGTI compounds as a These are with the that our GGTI RhoA, as a of J. Qian Y. Chen J. Hamilton A.D. Sebti S.M. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Qian Y. Hamilton A.D. Sebti S.M. Mol. Cell. Biol. 1998; PubMed Google Scholar, M.F. C.J. Nature. 1998; PubMed Scopus Google Scholar). These also with the of the accumulation of in GGTase-I-deficient cells from knock-out mice (6Sjogren A.K. Andersson K.M. Liu M. Cutts B.A. Karlsson C. Wahlstrom A.M. Dalin M. Weinbaum C. Casey P.J. Tarkowski A. Swolin B. Young S.G. Bergo M.O. J. Clin. Investig. 2007; 117: 1294-1304Crossref PubMed Scopus (93) Google Scholar). In this we have also reported the identification of a novel of These compounds share the with one of the GGTI compounds but an tail emanating from the core a of have been identified in the (26El Oualid F. Cohen L.H. van der Marel G.A. Overhand M. Curr. Med. Chem. 2006; 13: 2385-2427Crossref PubMed Scopus (29) Google Scholar). used inhibitors are however, the inhibition of RabGGTase of the compounds. In our compounds inhibit RabGGTase with a we inhibition of geranylgeranylation of Rab protein in modification of the compounds was to their cellular activity. Recent studies that may be valuable as A study small showed that the inhibition of RabGGTase to apoptosis induction in human cancer cells K. Chen C. H. Y. B. K. V. C. D. J.J. H. H. M. G. K. M. P. Cancer Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). of RabGGTase are in a number of human cancers K. Chen C. H. Y. B. K. V. C. D. J.J. H. H. M. G. K. M. P. Cancer Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). inhibitor compounds that inhibit RabGGTase of Rab protein and apoptosis K. Chen C. H. Y. B. K. V. C. D. J.J. H. H. M. G. K. M. P. Cancer Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). We have shown that our compounds inhibit the enzyme by competing with the substrate protein. our compounds are derived from GGTI and GGTI share the This may be the that both our GGTI and by competing with the substrate protein. GGTase-I and RabGGTase share (16Leung K.F. Baron R. Seabra M.C. J. Lipid Res. 2006; 47: 467-475Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar, Oualid F. Cohen L.H. van der Marel G.A. Overhand M. Curr. Med. Chem. 2006; 13: 2385-2427Crossref PubMed Scopus (29) Google Scholar); both have a core that of α- and In the corresponding subunits in these share be to these inhibitors to in these enzymes. the other we found that compounds a structural feature that is to this group of a characteristic aliphatic tail attached to the penta-substituted pyrrolidine core. be to this feature to the inhibition of RabGGTase. is that the aliphatic tail a or with an that is specific to RabGGTase but to GGTase-I. The significance of of REP for the RabGGTase has been O. Rak A. Reents R. Niculae A. Sidorovitch V. Cioaca M.D. Bessolitsyna E. Thoma N.H. Waldmann H. Schlichting I. Goody R.S. Alexandrov K. Mol. Cell. 2003; 11: 483-494Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar, O. Rak A. S. N.H. A.T. Brunsveld L. A. Waldmann H. Goody R.S. Alexandrov K. EMBO J. 2006; PubMed Scopus Google Scholar). Further characterization of our GGTI and to of the and in the of the two enzymes. In we have reported different types of inhibitors of protein geranylgeranylation. we reported novel inhibit proliferation of a variety of human cancer cell lines and cause G1 cell cycle we reported novel those compounds structural that this of In the of the identification of we also identified inhibitors that inhibit both GGTase-I and RabGGTase. of these novel compounds may to of the roles of protein geranylgeranylation. In may provide compounds for the development of the inhibition of protein geranylgeranylation. We and for the of GGTI cells and for breast cancer with