Disabling Receptor Ensembles with Rationally Designed Interface Peptidomimetics

Abstract

Members of the erbB family receptor tyrosine kinases (erbB1, erbB2, erbB3, and erbB4) are overexpressed in a variety of human cancers and represent important targets for the structure-based drug design. Homo- and heterodimerization (oligomerization) of the erbB receptors are known to be critical events for receptor signaling. To block receptor self-associations, we have designed a series of peptides derived from potential dimerization surfaces in the extracellular subdomain IV of the erbB receptors (erbB peptides). In surface plasmon resonance (BIAcore) studies, the designed peptides have been shown to selectively bind to the erbB receptor ectodomains and isolated subdomain IV of erbB2 with submicromolar affinities and to inhibit heregulin-induced interactions of erbB3 with different erbB receptors. A dose-dependent inhibition of native erbB receptor dimerization by the erbB peptides has been observed in 32D cell lines transfected with different combinations of erbB receptors. The peptides effectively inhibited growth of two types of transformed cells overexpressing different erbB receptors, T6-17 and 32D, in standard MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and cell viability assays. The study identifies distinct loops within the membrane-proximal part of the subdomain IV as potential receptor-receptor interaction sites for the erbB receptors and demonstrates the possibility of disabling receptor activity by structure-based targeting of the dimerization interfaces. Molecular models for possible arrangement of the erbB1·EGF complex, consistent with the involvement of subdomain IV in inter-receptor interactions, are proposed. Small dimerization inhibitors described herein can be useful as probes to elucidate different erbB signaling pathways and may be developed as therapeutic agents. Members of the erbB family receptor tyrosine kinases (erbB1, erbB2, erbB3, and erbB4) are overexpressed in a variety of human cancers and represent important targets for the structure-based drug design. Homo- and heterodimerization (oligomerization) of the erbB receptors are known to be critical events for receptor signaling. To block receptor self-associations, we have designed a series of peptides derived from potential dimerization surfaces in the extracellular subdomain IV of the erbB receptors (erbB peptides). In surface plasmon resonance (BIAcore) studies, the designed peptides have been shown to selectively bind to the erbB receptor ectodomains and isolated subdomain IV of erbB2 with submicromolar affinities and to inhibit heregulin-induced interactions of erbB3 with different erbB receptors. A dose-dependent inhibition of native erbB receptor dimerization by the erbB peptides has been observed in 32D cell lines transfected with different combinations of erbB receptors. The peptides effectively inhibited growth of two types of transformed cells overexpressing different erbB receptors, T6-17 and 32D, in standard MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and cell viability assays. The study identifies distinct loops within the membrane-proximal part of the subdomain IV as potential receptor-receptor interaction sites for the erbB receptors and demonstrates the possibility of disabling receptor activity by structure-based targeting of the dimerization interfaces. Molecular models for possible arrangement of the erbB1·EGF complex, consistent with the involvement of subdomain IV in inter-receptor interactions, are proposed. Small dimerization inhibitors described herein can be useful as probes to elucidate different erbB signaling pathways and may be developed as therapeutic agents. epidermal growth factor receptor epidermal growth factor human immunodeficiency virus type 1 glutathioneS-transferase phosphate-buffered saline 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide type-1 insulin-like growth factor receptor tumor necrosis factor interleukin-3 heregulin-β1 surface plasmon resonance erythropoietin erbB2 (neu, HER2) is a member of the epidermal growth factor or HER family of tyrosine kinase receptors that also includes erbB1 (EGFR,1 HER1), erbB3 (HER3), and erbB4 (HER4) (1Dougall W.C. Qian X. Peterson N.C. Miller M.J. Samanta A. Greene M.I. Oncogene. 1994; 9: 2109-2123PubMed Google Scholar, 2Hynes N.E. Stern D.F. Biochim. Biophys. Acta. 1994; 1198: 165-184Crossref PubMed Scopus (1008) Google Scholar, 3Reese D.M. Slamon D.J. Stem Cells. 1997; 15: 1-8Crossref PubMed Scopus (204) Google Scholar, 4Alroy I. Yarden Y. FEBS Lett. 1997; 410: 83-86Crossref PubMed Scopus (658) Google Scholar). Overexpression of erbB receptors has been found in many types of human cancer raising the possibility that receptor-directed therapies may be useful as cancer management strategies. Greater expression of erbB2 on transformed cells than on normal epithelial tissues allows selective targeting of tumor cells using various approaches (5Drebin J.A. Link V.C. Greene M.I. Oncogene. 1988; 2: 273-277PubMed Google Scholar, 6O'Rourke D.M. Greene M.I. Immunol. Res. 1998; 17: 179-189Crossref PubMed Scopus (6) Google Scholar, 7Murali R. Greene M.I. Immunol. Res. 1998; 17: 163-169Crossref PubMed Scopus (27) Google Scholar, 8O'Rourke D.M. Kao G.D. Singh N. Park B.W. Muschel R.J., Wu, C.J. Greene M.I. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 10842-10847Crossref PubMed Scopus (71) Google Scholar, 9O'Rourke D.M. Nute E.J. Davis J.G., Wu, C. Lee A. Murali R. Zhang H.T. Qian X. Kao C.C. Greene M.I. Oncogene. 1998; 16: 1197-1207Crossref PubMed Scopus (48) Google Scholar, 10Wels W. Harwerth I.M. Hynes N.E. Groner B. J. Steroid Biochem. Mol. Biol. 1992; 43: 1-7Crossref PubMed Scopus (14) Google Scholar, 11Zhang H. Wang Q. Montone K.T. Peavey J.E. Drebin J.A. Greene M.I. Murali R. Exp. Mol. Pathol. 1999; 67: 15-25Crossref PubMed Scopus (39) Google Scholar, 12Wels W. Harwerth I.M. Mueller M. Groner B. Hynes N.E. Cancer Res. 1992; 52: 6310-6317PubMed Google Scholar, 13Xu F.J. Boyer C.M. Bae D.S., Wu, S. Greenwald M. O'Briant K., Yu, Y.H. Mills G.B. Bast R.C., Jr. Int. J. Cancer. 1994; 59: 242-247Crossref PubMed Scopus (25) Google Scholar). A variety of strategies have also been developed for targeting the erbB1 receptor, including monoclonal antibodies, ligand-linked immunotoxins, tyrosine kinase inhibitors, and antisense approaches. Recently, we have reported the design of an anti-erbB2 peptide mimetic, AHNP, derived from the structure of the CDR-H3 loop of the anti-erbB2 monoclonal antibody 4D5 and demonstrated its in vitro and in vivo activities in disabling erbB2 tyrosine kinases similar to the monoclonal antibody (14Park B.W. Zhang H.T., Wu, C. Berezov A. Zhang X. Dua R. Wang Q. Kao G. O'Rourke D.M. Greene M.I. Murali R. Nat. Biotechnol. 2000; 18: 194-198Crossref PubMed Scopus (171) Google Scholar, 15Berezov A. Zhang H.-T. Greene M.I. Murali R. BIAjournal. 2001; 8: 4-7Google Scholar, 16Berezov A. Zhang H.-T. Greene M.I. Murali R. J. Med. Chem. 2001; 44: 2565-2574Crossref PubMed Scopus (92) Google Scholar). We have argued that another interesting approach for disabling erbB receptor activity would be targeting protein-protein interaction surfaces. Because protein-protein interactions play a key role in various mechanisms of cellular growth and differentiation, and viral replication, inhibition of these interactions is a promising novel approach for rational drug design against a wide number of cellular and viral targets (17Zutshi R. Brickner M. Chmielewski J. Curr. Opin. Chem. Biol. 1998; 2: 62-66Crossref PubMed Scopus (104) Google Scholar, 18Peczuh M.W. Hamilton A.D. Chem. Rev. 2000; 100: 2479-2494Crossref PubMed Scopus (525) Google Scholar). Synthetic peptides that disrupt protein-protein interactions have been successfully shown to act as inhibitors of HIV-1 protease (19Schramm H.J. Boetzel J. Buttner J. Fritsche E. Gohring W. Jaeger E. Konig S. Thumfart O. Wenger T. Nagel N.E. Schramm W. Antiviral Res. 1996; 30: 155-170Crossref PubMed Scopus (81) Google Scholar), HIV-1 reverse transcriptase (20Divita G. Restle T. Goody R.S. Chermann J.C. Baillon J.G. J. Biol. 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In the we have the to inhibit erbB receptor that protein-protein interactions can be inhibited by peptides that the key the We have distinct extracellular of erbB2 that are in heterodimerization with erbB1 T. Davis J.G. T. O'Rourke D.M. Greene M.I. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar). In we found that the part of subdomain IV the signaling and activities by with a therapeutic potential for subdomain as a for We a rational design of peptides derived from the extracellular subdomain IV of erbB receptors (erbB and that these peptides can bind to the receptors of the erbB family and inhibit receptor peptides from the of and by and using a The peptides by in to with and of the by of with of a peptide and of to of and with the The peptides and by using a of than for the of 1 have been for peptide and to be to the or by using for peptide as described in a study Biochem. PubMed Scopus Google Scholar). The the subdomain IV of erbB2 by The and the two designed to for the to of the with of the and of to the the of and for The cells by for and with of and the of 1 and 1 on to the of and the for 1 and for of to the for and with of by for for 1 and of the and Binding with the surface plasmon of erbB2 receptor by of erbB1 and erbB3, as described in a study M.J. J. 2000; PubMed Scopus Google Scholar), by A. of and of of of the erbB receptors in the surface the standard to of a and a of to on the in the surface a of the and by the of of 1 The of receptor resonance A surface the receptor and as a to for and and to the receptors on the in of an of the peptide to the receptor, by a which the is the and the peptide is the receptor The MTT has been for cell growth as described J. Immunol. PubMed Scopus Google Scholar). T6-17 cells in in T6-17 is derived from by overexpressing the human erbB2 in of 1 erbB peptides for for of different in the activity be by the of MTT in to and of of the of an the using an 32D cell with erbB receptors from H. of in and interleukin-3 and and M. Wang Lee C.C. A. M. P. C. M. J.H. J. 1997; 16: PubMed Scopus Google Scholar). The and cells with erbB peptides for or or 32D and for The cell viability with by the cells in and and with erbB peptides for or and for with and in for The cell with anti-erbB2 or antibody and with To the the to the of erbB receptors using the for by the from of and erbB1 with design on the of of for and insulin-like growth receptor for The using the by of and to the of the for the models by using from the for of the for peptide that have a in the by and or by loop using a H. R. C. Sci. 1997; PubMed Scopus Google Scholar, R. Sci. 1996; PubMed Scopus Google The by the in the To a erbB1·EGF the on the erbB1·EGF has a J.E. M. I. D.M. J. J. 1997; 16: PubMed Scopus Google Scholar, M. I. J. J. Biochem. 1997; PubMed Scopus Google the part of subdomain IV is a interaction on described the of is to of erbB1 Proc. Natl. Acad. Sci. U. S. A. 1992; PubMed Scopus Google the of is to of erbB1 J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google the of to erbB1 is to from the surface J.G. Biochemistry. PubMed Scopus Google of erbB1 are for the and for the J.E. M. I. D.M. J. J. 1997; 16: PubMed Scopus Google to the of subdomain V.C. Sci. 2000; 9: PubMed Scopus Google Scholar). of two erbB1 and two to the on two different models of the arrangement The models using the models have a and may have a of in the of the with to In the we have designed peptides derived from the of subdomain IV that inter-receptor interactions the erbB family The peptides designed on the of the subdomain IV of erbB receptors by with the subdomain of the type-1 insulin-like growth factor receptor M. M.J. Nature. 1998; PubMed Scopus Google Scholar), as as of the receptor and that have similar peptides the from and from from and from derived from the membrane-proximal of A as a the models of the subdomain of and peptides derived from the part of is a peptide that part of the is a peptide by two and a by the Molecular the peptides and loops of the The designed erbB peptides have been for to erbB receptors by of surface plasmon resonance (BIAcore) A for of peptide to erbB receptors on the is shown in A. by of the to the interaction which a and of on a of for the of to the a interaction the peptide and the for erbB in a similar as are in erbB peptides to different erbB receptors. be to receptor as a of erbB peptides to the erbB receptor A peptide bind to of the receptors. Binding also be observed for different peptides within the erbB bind to the erbB1 receptor than to erbB2 and to the peptide the to to the extracellular of the receptors by surface plasmon in a Binding to the extracellular of the receptors by surface plasmon To that erbB peptides bind to of erbB receptors, we interaction of the peptide with on the surface The observed to similar and as to the of erbB2 A and of erbB peptides to IV from to the erbB2 that subdomain IV is the for erbB Because erbB peptides are derived from subdomain IV of different erbB receptors, involvement of subdomain IV in receptor-receptor interactions the of erbB receptor To study the of erbB peptides on receptor self-associations, we have developed a in which the ectodomains of erbB receptors on the surface and the of erbB3 or in the of We a of receptor-receptor interactions of these in the of erbB3 with a of a to erbB receptors observed and of the erbB receptor in with observed for the receptor as a In a we to similar receptor be observed for the erbB1 receptor in the of or growth factor interaction of the erbB1 with the receptors be in the or in the of the erbB1 that erbB1 receptor dimerization is of the erbB peptides on heregulin-induced receptor by using the of the by of as described The of on receptor is shown in The peptide effectively inhibited of erbB3 to receptors. The of inhibition observed for the by and a the or a peptide of the erbB peptides and on receptor for different erbB peptides are in from the for the which the to erbB1 is in disabling interaction of erbB3 with erbB1 than with receptors with the is the of erbB3 with the to the erbB receptors is an of and interactions derived from the of erbB2, the on the of erbB3 to which with the with receptors of receptor dimerization by of peptides on the of to the receptors in the of of peptides on the of to the receptors in the of in a of the erbB peptides on dimerization of native erbB receptors has been using the 32D cell lines transfected with different erbB receptors. cells transfected with with erbB2 and erbB3, and with erbB2 and the of and on the heregulin-induced receptor in the a dimerization A observed for the peptide as a The observed inhibition of receptor dimerization by dose-dependent with an of of and on receptor dimerization have been observed in the cells activity of erbB peptides by to inhibit cell using standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide J. Immunol. PubMed Scopus Google Scholar). transformed tumor cells for (14Park B.W. Zhang H.T., Wu, C. Berezov A. Zhang X. Dua R. Wang Q. Kao G. O'Rourke D.M. Greene M.I. Murali R. Nat. Biotechnol. 2000; 18: 194-198Crossref PubMed Scopus (171) Google Scholar). In MTT the peptides inhibited the growth of T6-17 an transformed cell from to The activity of erbB peptides the of 1 is shown in an of peptides on cell which has the erbB2 also the peptide in the MTT To the observed activities of erbB2 peptides against T6-17 cells with receptor or activity on receptor-receptor interactions, we have the shown in and the MTT shown in for peptides is a the activity and to erbB2, with affinities to erbB receptors and and a has been observed the activity and activity against interactions, against or interactions of the erbB peptides on cells overexpressing erbB receptors has been using the 32D cell of 32D cells with erbB receptors the of in a and or cell A. M. M.C. Lee C.C. V. N. J.H. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: PubMed Scopus Google Scholar). A the of different erbB peptides on the viability of the 32D in the erbB The observed for the cells in the The on the and cells in the also the cell lines in the on cell viability be for of the peptides that the observed inhibition of cell by the erbB peptides is by on the erbB receptor signaling on signaling. we have shown that peptides derived from the extracellular of different erbB receptors can bind to the receptors of the erbB family and inhibit receptor The on receptor-receptor interactions have been demonstrated for the ectodomains in and for the native receptors in 32D cell lines The observed of receptor-receptor interactions in the of growth in cells overexpressing erbB receptors and and of the native erbB receptors has been and on of the extracellular of these receptors are In and studies, has been demonstrated for erbB1 and erbB4 M.J. 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Biochemistry. 2000; PubMed Scopus Google are and in The of the erbB receptors be similar to the for the receptor of I. 1999; PubMed Scopus Google Scholar), the receptor as an an of erbB peptides described in study represent of the loops or in the subdomain IV of the erbB receptors on studies, a of with the receptor is a that the interactions observed for the erbB peptides can also be by the sites of the native erbB receptors and play a role in In for the peptide is designed erbB a loop a membrane-proximal of the erbB2 the of erbB2 can bind to erbB receptors is also to be from the native erbB2 The that the designed erbB peptides are to erbB receptor are to the erbB family that the part of subdomain IV is a receptor-receptor interaction by erbB receptors. Because erbB peptides bind to the receptor and to erbB receptors these sites can in and A variety of possible in which receptors can has been demonstrated for the O. 1999; PubMed Scopus Google Scholar, R.S. C. J.C. B. H. Zhang J. J. S. 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Immunol. 2000; PubMed Scopus Google in various in vitro and in vivo of the the observed inter-receptor interactions the of subdomain IV are an important role in the receptor inhibition of these interactions by the erbB peptides in a of the cell growth and The of the by erbB peptides has been demonstrated in different erbB cell Because T6-17 cells are by overexpressed of erbB2 receptor of erbB receptors, erbB2 of erbB peptides are to be important of on T6-17 cell growth than erbB1 or erbB3 peptides to erbB2 and inhibition of and activity against T6-17 cells in the MTT in these the observed activities of erbB peptides are by to the erbB2 receptor and by receptor-receptor interactions that erbB2, erbB2 is by the that affinities for erbB receptors and which are in T6-17 have on activity the of peptides to block receptor-receptor that erbB2 as and is also for activity in the MTT erbB inhibition of cell growth in 32D cells transfected with erbB receptors has also been shown to be by the erbB receptor inhibition of cell growth has been observed the cells in the erbB In inhibition an erbB the cells in the In we have shown that erbB receptor signaling can be inhibited by designed peptide derived from the subdomain IV of erbB receptor The bind to the receptors of the erbB family and block inter-receptor interactions, which leads to the growth inhibition of cells in Because erbB receptors represent a therapeutic peptide that selectively bind to receptor family and activity have an that are to a member of the erbB The study also demonstrates the of the part of subdomain IV for receptor-receptor interactions in signaling by erbB family We the of Cancer and Cancer for the the and of of for with studies, and the of for peptide and