Inhibition of Furin/Proprotein Convertase-catalyzed Surface and Intracellular Processing by Small Molecules

Furin is a ubiquitously expressed proprotein convertase (PC) that plays a vital role in numerous disease processes including cancer metastasis, bacterial toxin activation (e.g. anthrax and Pseudomonas), and viral propagation (e.g. avian influenza and human immunodeficiency virus). To identify small molecule inhibitors of furin and related processing enzymes, we performed high-throughput screens of chemical diversity libraries utilizing both enzyme-based and cell-based assays. The screens identified partially overlapping sets of compounds that were further characterized for affinity, mechanism, and efficacy in additional cellular processing assays. Dicoumarols were identified as a class of compounds that inhibited furin non-competitively and reversibly with Ki values in the micromolar range. These compounds inhibited furin/furin-like activity both at the cell surface (protecting against anthrax toxin) and in the secretory pathway (blocking processing of the metastasis factor membrane-type 1 matrix metalloproteinase/MT1-MMP) at concentrations close to Ki values. Compounds tested exhibited distinct patterns of inhibition of other furin-family PCs (rat PACE4, human PC5/6 and human PC7), showing that dicoumarol derivatives might be developed as either generic or selective inhibitors of the PCs. The extensive clinical use, high bioavailability and relatively low toxicity of dicoumarols suggests that the dicoumarol structure will be a good starting point for development of drug-like inhibitors of furin and other PCs that can act both intracellularly and at the cell surface. Furin is a ubiquitously expressed proprotein convertase (PC) that plays a vital role in numerous disease processes including cancer metastasis, bacterial toxin activation (e.g. anthrax and Pseudomonas), and viral propagation (e.g. avian influenza and human immunodeficiency virus). To identify small molecule inhibitors of furin and related processing enzymes, we performed high-throughput screens of chemical diversity libraries utilizing both enzyme-based and cell-based assays. The screens identified partially overlapping sets of compounds that were further characterized for affinity, mechanism, and efficacy in additional cellular processing assays. Dicoumarols were identified as a class of compounds that inhibited furin non-competitively and reversibly with Ki values in the micromolar range. These compounds inhibited furin/furin-like activity both at the cell surface (protecting against anthrax toxin) and in the secretory pathway (blocking processing of the metastasis factor membrane-type 1 matrix metalloproteinase/MT1-MMP) at concentrations close to Ki values. Compounds tested exhibited distinct patterns of inhibition of other furin-family PCs (rat PACE4, human PC5/6 and human PC7), showing that dicoumarol derivatives might be developed as either generic or selective inhibitors of the PCs. The extensive clinical use, high bioavailability and relatively low toxicity of dicoumarols suggests that the dicoumarol structure will be a good starting point for development of drug-like inhibitors of furin and other PCs that can act both intracellularly and at the cell surface. Furin, is a subtilisin-related serine protease and member of the proprotein convertase (PCs) 4The abbreviations used are:PCproprotein convertaseMT1-MMPmembrane-type 1 matrix metalloproteinaseHTShigh-throughput screeningrrathhumanssfurinsecreted, soluble human furindecRVKR-CMKdecanoyl-Arg-Val-Lys-Arg-chloromethylketoneboc-RVRR-MCAN-tert-butoxycarbonyl-Arg-Val-Arg-Arg-methylcoumarin amideboc-IEGR-MCAboc-Ile-Glu-Gly-Arg-MCAAMC7-amino-4-methyl coumarinpNApara-nitroanilideac-RVRR-pNAacetyl-Arg-Val-Arg-Arg-pNACHOChinese hamster ovaryRB*modified Ringer's bufferPAanthrax protective antigenATanthrax toxinMes4-morpholineethanesulfonic acidHAhemagglutinin. family that functions within the secretory and endocytic pathways and at the cell surface, cleaving proproteins at clusters of basic residues, typically of the form RX(K/R)R↓ (for reviews see Refs. 1.Rockwell N.C. Krysan D.J. Komiyama T. Fuller R.S. Chem. Rev. 2002; 102: 4525-4548Crossref PubMed Scopus (171) Google Scholar, 2.Thomas G. Nat. Rev. Mol. Cell Biol. 2002; 3: 753-766Crossref PubMed Scopus (975) Google Scholar, 3.Scamuffa N. Calvo F. Chretien M. Seidah N.G. Khatib A.M. FASEB J. 2006; 20: 1954-1963Crossref PubMed Scopus (191) Google Scholar). The specificity of furin and its yeast homologue Kex2 correlate well with the three-dimensional structures of their catalytic domains (4.Henrich S. Cameron A. Bourenkov G.P. Kiefersauer R. Huber R. Lindberg I. Bode W. Than M.E. Nat. Struct. Biol. 2003; 10: 520-526Crossref PubMed Scopus (301) Google Scholar, 5.Holyoak T. Wilson M.A. Fenn T.D. Kettner C.A. Petsko G.A. Fuller R.S. Ringe D. Biochemistry. 2003; 42: 6709-6718Crossref PubMed Scopus (91) Google Scholar). Ubiquitously expressed, furin has numerous known or suspected physiological substrates that include growth factors, receptors, coagulation proteins, plasma proteins (e.g. pro-von Willebrand factor), extracellular matrix components, and protease precursors (e.g. matrix metalloproteases) (2.Thomas G. Nat. Rev. Mol. Cell Biol. 2002; 3: 753-766Crossref PubMed Scopus (975) Google Scholar). Although the homozygous furin knock-out mouse exhibits embryonic lethality (6.Roebroek A.J. Umans L. Pauli I.G. Robertson E.J. van Leuven F. Van de Ven W.J. Constam D.B. Development. 1998; 125: 4863-4876Crossref PubMed Google Scholar), analysis of liver-specific ablation suggests functional overlap with other PCs, such as PACE4, PC5/6, and PC7, that are also widely expressed and act in the constitutive secretory pathway (7.Roebroek A.J. Taylor N.A. Louagie E. Pauli I. Smeijers L. Snellinx A. Lauwers A. Van de Ven W.J. Hartmann D. Creemers J.W. J. Biol. Chem. 2004; 279: 53442-53450Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). Furin activity contributes to numerous chronic pathological conditions, including Alzheimer disease (8.Bennett B.D. Denis P. Haniu M. Teplow D.B. Kahn S. Louis J.C. Citron M. Vassar R. J. Biol. Chem. 2000; 275: 37712-37717Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar), other non-Alzheimer cerebral amyloidoses (9.Rostagno A. Tomidokoro Y. Lashley T. Ng D. Plant G. Holton J. Frangione B. Revesz T. Ghiso J. Cell Mol. Life Sci. 2005; 62: 1814-1825Crossref PubMed Scopus (56) Google Scholar), osteoarthritis (10.Arner E.C. Curr. Opin. Pharmacol. 2002; 2: 322-329Crossref PubMed Scopus (142) Google Scholar), atherosclerosis (11.Stawowy P. Fleck E. J. Mol. Med. 2005; 83: 865-875Crossref PubMed Scopus (41) Google Scholar), and tumor progression and malignancy (12.Bassi D.E. Fu J. Lopez de Cicco R. Klein-Szanto A.J. Mol. Carcinog. 2005; 44: 151-161Crossref PubMed Scopus (202) Google Scholar). Moreover, activation by host cells of bacterial toxins such as anthrax toxin, Pseudomonas exotoxin A, diphtheria toxin (13.Gordon V.M. Klimpel K.R. Arora N. Henderson M.A. Leppla S.H. Infect. Immun. 1995; 63: 82-87Crossref PubMed Google Scholar), Shiga toxin (14.Garred O. van Deurs B. Sandvig K. J. Biol. Chem. 1995; 270: 10817-10821Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar), and Bordetella dermonecrotic toxin (15.Matsuzawa T. Fukui A. Kashimoto T. Nagao K. Oka K. Miyake M. Horiguchi Y. J. Biol. Chem. 2004; 279: 2866-2872Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar), requires cleavage by furin or other PCs. Furin or furin-like cleavage of viral envelope glycoproteins is necessary for propagation of many lipid-enveloped viral pathogens including H5N1 avian influenza (16.Basak A. Zhong M. Munzer J.S. Chretien M. Seidah N.G. Biochem. J. 2001; 353: 537-545Crossref PubMed Scopus (90) Google Scholar), human immunodeficiency virus-1 (17.Moulard M. Decroly E. Biochim. Biophys. Acta. 2000; 1469: 121-132Crossref PubMed Scopus (117) Google Scholar), ebola (18.Volchkov V.E. Feldmann H. Volchkova V.A. Klenk H.D. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 5762-5767Crossref PubMed Scopus (413) Google Scholar), measles (19.Watanabe M. Hirano A. Stenglein S. Nelson J. Thomas G. Wong T.C. J. Virol. 1995; 69: 3206-3210Crossref PubMed Google Scholar), cytomegalovirus (20.Jean F. Thomas L. Molloy S.S. Liu G. Jarvis M.A. Nelson J.A. Thomas G. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 2864-2869Crossref PubMed Scopus (67) Google Scholar), and flaviviruses (21.Stadler K. Allison S.L. Schalich J. Heinz F.X. J. Virol. 1997; 71: 8475-8481Crossref PubMed Google Scholar). Even non-enveloped viruses, such as human papillomavirus, can require furin-type processing for entry into the cyotsol after endocytosis (22.Richards R.M. Lowy D.R. Schiller J.T. Day P.M. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 1522-1527Crossref PubMed Scopus (265) Google Scholar). proprotein convertase membrane-type 1 matrix metalloproteinase high-throughput screening rat human secreted, soluble human furin decanoyl-Arg-Val-Lys-Arg-chloromethylketone N-tert-butoxycarbonyl-Arg-Val-Arg-Arg-methylcoumarin amide boc-Ile-Glu-Gly-Arg-MCA 7-amino-4-methyl coumarin para-nitroanilide acetyl-Arg-Val-Arg-Arg-pNA Chinese hamster ovary modified Ringer's buffer anthrax protective antigen anthrax toxin 4-morpholineethanesulfonic acid hemagglutinin. The multiple roles for furin in human pathophysiology have made it a target of interest for development of therapeutic agents. Numerous protein- and peptide-based furin inhibitors have been devised (23.Fugere M. Day R. Trends Pharmacol. Sci. 2005; 26: 294-301Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar). For the most part, these are not drug-like and their use as pharmaceutical agents is hampered by large size, instability, toxicity, and/or low cell permeability. Recently, 2,5-dideoxystreptamine derivatives have shown promise (24.Jiao G.S. Cregar L. Wang J. Millis S.Z. Tang C. O'Malley S. Johnson A.T. Sareth S. Larson J. Thomas G. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 19707-19712Crossref PubMed Scopus (79) Google Scholar), although these molecules have yet to be examined for inhibition of intracellular processing. Important pathophysiological roles exist for furin at the cell surface, such as in the processing of anthrax protective antigen. However, maturation of other bacterial toxins, viral envelope glycoproteins, and metalloprotease precursors such as membrane-type 1 matrix metalloproteinase (MT1-MMP), a matrix metalloprotease whose activity contributes directly to degradation of extracellular matrix components and is important for angiogenesis, tumor invasion, and metastasis (25.Sato H. Takino T. Miyamori H. Cancer Sci. 2005; 96: 212-217Crossref PubMed Scopus (159) Google Scholar), require processing by furin in the trans Golgi network and endosomal compartments (2.Thomas G. Nat. Rev. Mol. Cell Biol. 2002; 3: 753-766Crossref PubMed Scopus (975) Google Scholar, 26.Yana I. Weiss S.J. Mol. Biol. Cell. 2000; 11: 2387-2401Crossref PubMed Scopus (275) Google Scholar). Here we report identification of drug-like small molecule inhibitors through simultaneous high-throughput screening (HTS) of chemical diversity libraries with both enzyme-based and cell-based assays for furin and furin-like activities. A preliminary report of the cell-based assay has been published elsewhere (27.Coppola J.M. C.A. B.D. A. Biochem. PubMed Scopus Google Scholar). the of the with the cellular identification of small molecule compounds with the of high affinity, high cell and low have extensive F. F. N. L. E. Curr. Med. Chem. 2005; PubMed Scopus Google Scholar), were identified in as a family of compounds that inhibited furin reversibly and also inhibited rat human PC5/6 and and both extracellular maturation of anthrax protective antigen and intracellular processing of and other soluble human furin T. Fuller R.S. Biochemistry. 2000; PubMed Scopus Google Scholar, Fuller R.S. J. Biol. Chem. Full Text PDF PubMed Google and and human M. F. P. K. R. Day R. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google were expressed and as N-tert-butoxycarbonyl-Arg-Val-Arg-Arg-methylcoumarin amide and boc-Ile-Glu-Gly-Arg-MCA were of and compounds and were Compounds and were Compounds and were Compounds (27.Coppola J.M. C.A. B.D. A. Biochem. PubMed Scopus Google and were and characterized as J.M. B.D. A. 10: PubMed Scopus Google Scholar). compounds were in to as (27.Coppola J.M. C.A. B.D. A. Biochem. PubMed Scopus Google Scholar). including libraries were by the for of The cell assay and factor were as T. J.A. Fuller R.S. 2005; PubMed Scopus Google Scholar). 1 and or buffer the into of into the a of were to the The in buffer or the as were by the of 7-amino-4-methyl coumarin a high-throughput were for identification and to compounds by of and values for for were T.D. K.R. J. PubMed Scopus Google Scholar). with were Compounds with inhibition were as Compounds inhibition of other in the of the for were analysis to The enzyme-based assay compounds in the were as of enzyme-based and cell-based assays for a are shown in that and as for the to be identified in the cell-based For compounds were in into and furin buffer and performed to concentrations of to in were by analysis performed and assays were performed as (27.Coppola J.M. C.A. B.D. A. Biochem. PubMed Scopus Google Scholar). these assays inhibition of cleavage of a expressed in Chinese hamster ovary of to the and domains of through a acid furin (27.Coppola J.M. C.A. B.D. A. Biochem. PubMed Scopus Google Scholar). Furin cleavage in of can be in the cells were in with 1 and were with cells were in modified with and were at with as Fuller R.S. J. Biol. Chem. Full Text PDF PubMed Google Scholar). assays were performed in furin assay buffer 1 T. Fuller R.S. Biochemistry. 2000; PubMed Scopus Google by with inhibitors at a of concentrations for at to and its of for values were a M. E. Scholar). of these that the dicoumarols and were compounds and were inhibitors not the of inhibition assays were by with inhibitors inhibitors to However, to reversibly after into in inhibitors were into assay buffer and for to of and were Dicoumarols also exhibited with the the at concentrations or the of Ki values A Scholar). The dicoumarols were also To these we performed inhibition assays the use of concentrations at high The of for to be at a in compounds were into assay buffer and for and were and inhibition were for concentrations were to and inhibitors were at concentrations that Ki to were performed in and at To inhibition and Ki activity a of that by The were for or inhibition used to Ki values and the for dicoumarol inhibitors and compounds and Ki values in were to values To inhibition of and examined in furin assay buffer with furin in furin assay buffer as a To assay processing of the intracellular cells were in with the is a of rat in the cleavage at has been to a for furin A. 10: PubMed Scopus Google Scholar). with or and with or and cells were and by toxin assays were performed as T. J.A. Fuller R.S. 2005; PubMed Scopus Google as cells were with modified Ringer's buffer J.A. Cell. 2000; 2: PubMed Scopus Google and with or compounds to be tested at toxin and factor cells were for and cells were the cell assay were a and of and cells were to performed as G. B. Thomas J. J.M. L. D. B.D. A. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: PubMed Scopus Google Scholar). the assay A a mouse to were with by with or processing a For were and a and or and by For processing the were and The of the by the of the for the to the The in the in the of compounds were to values were expressed as inhibition and against values were as the of to processing by to were in the of compounds that inhibited furin and were within the Golgi we that the and a that a cell assay for furin and furin-like activities. The assay cleavage of a by secreted, T. Fuller R.S. Biochemistry. 2000; PubMed Scopus Google Scholar, Fuller R.S. J. Biol. Chem. Full Text PDF PubMed Google Scholar). The cellular assay cells a trans Golgi furin whose cleavage by furin or other PCs in of soluble (27.Coppola J.M. C.A. B.D. A. Biochem. PubMed Scopus Google Scholar). of the screens are assays were used to small molecule diversity libraries and with by inhibition of of the screens were further to and were by in of compounds that were characterized in with compounds and identified by screening against the yeast furin and with and of compounds identified in the of the compounds the and were derivatives of dicoumarol and other dicoumarol derivatives not identified in the and were and also to of of the inhibitors shown in were characterized by values a with as a analysis of these by that of the dicoumarols and inhibited by a and that the basic compounds and were inhibitors not The dicoumarol compounds and compounds and were characterized to Ki values as a to with and These were to for and of inhibition a for and and a for and of Ki or inhibition for and in the inhibition a Ki for for the other dicoumarols and not in the inhibition a Ki for that the dicoumarol compounds by a is The other basic compounds also to be were not characterized in The dicoumarol compounds exhibited Ki values for that to and exhibited inhibition in the that the dicoumarol structure is for The compounds exhibited Ki values to of for derivatives in a of by dicoumarol compounds with at Ki in the of and into buffer activity in of that for such of activity into a at Ki of with and for to also of not Furin and furin-like act at the cell surface to the form of anthrax protective antigen to the the that and of anthrax factor and factor J.A. Rev. Cell Biol. 2003; PubMed Scopus Google Scholar). of furin activity against anthrax toxicity by and factor T. J.A. Fuller R.S. 2005; PubMed Scopus Google Scholar, Leppla S.H. Lindberg I. Infect. Immun. 2004; PubMed Scopus Google Scholar). T. J.A. Fuller R.S. 2005; PubMed Scopus Google Scholar), of factor of within of cells exhibited Compounds and cell and exhibited distinct and exhibited at showing toxicity at and exhibited at with of cells with in the of concentrations of the of cells with or or of To that to inhibition of we tested of the to processing of to were with for and cell were by with of to cells were with or at concentrations to Ki or at concentrations to cleavage of To inhibition of intracellular processing by furin or other PCs, we cell assays the furin A. 10: PubMed Scopus Google Scholar). is a to a furin cleavage at is a to a furin cleavage at of in cells in the of both and of the in the extracellular of these cells with compounds in a in the form and in the form The compounds tested a of with and values of and The compounds tested in also inhibited intracellular processing of pro-von Willebrand factor not of maturation of a important to tumor and metastasis (25.Sato H. Takino T. Miyamori H. Cancer Sci. 2005; 96: 212-217Crossref PubMed Scopus (159) Google Scholar). To compounds identified in processing of cells were with a the of furin of in cells in the of the and of as shown by analysis of and in in the of of to as and expressed as a of these cells with compounds inhibited processing. with with with with and with the well characterized furin inhibitors and Thomas L. J.S. Thomas G. J. Biol. Chem. Full Text PDF PubMed Google Scholar), the by inhibited processing by and To the of these compounds we cells with a soluble the J. H. Takino T. M. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar), is to the form by furin I. Weiss S.J. Mol. Biol. Cell. 2000; 11: 2387-2401Crossref PubMed Scopus (275) Google Scholar). shown by analysis processing of by in cells in of the form of in cell and extracellular of or in a of in cell with that with with to the A of compounds tested against catalytic domains of and other of the family in the constitutive secretory the endocytic and/or the cell surface and Ki values are shown in Although compounds tested inhibited and exhibited a of and exhibited Ki values for and for inhibited PCs with its activity against exhibited and and with compounds also inhibited human to or for inhibition of and by small molecule for for in a examined by with compounds for to derivatives and toxicity with at Ki for toxicity with at of small molecule inhibitors in cell of of inhibition of in a processing of for both chronic and human disease G. S. I. Pharmacol. PubMed Scopus Google Scholar). a large of processing are by PCs, these have as important (23.Fugere M. Day R. Trends Pharmacol. Sci. 2005; 26: 294-301Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar). that are not be in the of extracellular processing such as maturation of anthrax protective antigen. small molecules with high bioavailability and cell and low toxicity are to processing in intracellular Furin, PACE4, PC5/6, and in the constitutive secretory in the endocytic and/or at the cell surface and (2.Thomas G. Nat. Rev. Mol. Cell Biol. 2002; 3: 753-766Crossref PubMed Scopus (975) Google Scholar). of their patterns of and at overlap in it is the of development pathophysiological of furin or furin-like processing be inhibitors a high of family or generic inhibitors that can of the PCs. Here we report the of a high-throughput for small molecule inhibitors of that simultaneous use of and cellular assays. of the cell-based assay identified compounds that inhibited intracellular processing by furin or by furin with other PCs compounds with of the assay identified compounds that directly inhibited The of assays to furin inhibitors that high promise for intracellular The screens identified a of inhibitors that were and a of of the inhibitors were basic compounds that performed to toxicity or cell further cell-based assays were the of were related or to of these compounds as furin inhibitors is for to other furin inhibitors have been inhibition by of these compounds and that these molecules not with dicoumarols have extensive of use as agents that starting point for has been used as with activity to that of D. C. J. Pharmacol. PubMed Scopus Google Scholar, S. S. M. A. P. P. S. G. B. O. E. N. J. Med. 1997; PubMed Scopus Google Scholar, Med. 2006; Google Scholar). A large of dicoumarol derivatives have been and for activity M. M. J. Med. Chem. 3: PubMed Scopus Google Scholar). The use of dicoumarol as is of high low toxicity, and high cell permeability. dicoumarols examined exhibited high cell as the values for inhibition of intracellular processing were close to the Ki values with Although the furin inhibitors identified in exhibited Ki values in the micromolar their concentrations for inhibition of both cell surface and intracellular processing were also in the low micromolar range. of intracellular processing by other characterized furin including proteins (20.Jean F. Thomas L. Molloy S.S. Liu G. Jarvis M.A. Nelson J.A. Thomas G. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 2864-2869Crossref PubMed Scopus (67) Google Scholar, T. B. M. Day R. Fuller R.S. Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google and F. K. Thomas L. Liu G. Y. A.J. Thomas G. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: PubMed Scopus Google Scholar, S. H. E. Klenk H.D. W. PubMed Scopus Google Scholar), has concentrations to values for inhibition of intracellular processing by and were and 1 and Moreover, values for characterized furin inhibitors in processing have also been high in to Ki Ki for T. J.A. Fuller R.S. 2005; PubMed Scopus Google Scholar), Ki for T. J.A. Fuller R.S. 2005; PubMed Scopus Google Scholar), Ki for Than M.E. J. S. G. Bode W. Lindberg I. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar), and Ki for derivatives (24.Jiao G.S. Cregar L. Wang J. Millis S.Z. Tang C. O'Malley S. Johnson A.T. Sareth S. Larson J. Thomas G. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 19707-19712Crossref PubMed Scopus (79) Google Scholar). values for inhibition of intracellular processing by and were 1 and and of inhibition be related to the of these compounds to both the intracellular and surface of processing Although the therapeutic target of dicoumarols used as is R. Trends Mol. Med. 2004; 10: Full Text Full Text PDF PubMed Scopus Google Scholar), has also been shown to be a target G. O. P. J. Y. Biochemistry. 2006; PubMed Scopus Google Scholar). dicoumarol has been to in cells K. D. F. Biochem. Biophys. 2005; PubMed Scopus Google and of in in Golgi and A. R.S. A. G. D. M.A. A. J. Cell Biol. 2004; 83: PubMed Scopus Google Scholar). These or not the toxicity of dicoumarol have not clinical The PCs a of physiological for inhibition by dicoumarol and its of the functional of the PCs, it is to inhibition of processing in the cellular assays of anthrax Willebrand or is to inhibition of inhibition of other family or both that compounds can multiple of the family and that can be through of the dicoumarol structure For of the compounds concentrations for inhibition in cellular assays are to the therapeutic of that be close to that for dicoumarols multiple target enzymes, of compounds will be a good for that might compounds with for furin and other PCs. both for PCs and for PCs other (e.g. and further of derivatives also in the dicoumarol within furin and the of S. S. and J. for and J. for and R. and S. and the for Life of for

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