Current status of the development of Ras inhibitors

Journal of Biochemistry

Volumn 158, Issue 2, 2015, Pages 91-99

  Shima, Fumi ^a   Matsumoto, Shigeyuki ^a   Yoshikawa, Yoko ^a   Kawamura, Takashi ^a   Isa, Masayuki ^a   Kataoka, Tohru ^a  

^a KOBE UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

Author keywords

Anti cancer drugs; Drug design; NMR; Ras; Structurebased; X ray crystallography

Indexed keywords

GUANINE NUCLEOTIDE EXCHANGE FACTOR; GUANOSINE DIPHOSPHATE; GUANOSINE TRIPHOSPHATE; PROTEIN INHIBITOR; RAS PROTEIN; ENZYME INHIBITOR; PROTEIN BINDING;

CELL MEMBRANE; CONFORMATIONAL TRANSITION; DRUG DESIGN; MOLECULAR RECOGNITION; NONHUMAN; PROTEIN FUNCTION; PROTEIN INTERACTION; PROTEIN PROCESSING; PROTEIN TERTIARY STRUCTURE; REVIEW; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMICAL STRUCTURE; CHEMISTRY; DRUG EFFECTS; HUMAN; METABOLISM; SIGNAL TRANSDUCTION;

ANIMALS; ENZYME INHIBITORS; HUMANS; MODELS, MOLECULAR; PROTEIN BINDING; RAS PROTEINS; SIGNAL TRANSDUCTION;

EID: 84939637623     PISSN: 0021924X     EISSN: 17562651     Source Type: Journal    
DOI: 10.1093/jb/mvv060     Document Type: Review

References (62)

1. Wennerberg, K., Rossman, K.L., and Der, C.J. (2005) The Ras superfamily at a glance. J. Cell Sci. 118, 843-846
2. Knrnoub, A.E. and Weinberg, R.A. (2008) Ras oncogenes: split personalities. Nat. Rev. Mol. Cell Biol. 9, 517-531
3. Vetter, I.R. and Wittinghofer, A. (2001) The guanine nucleotide-binding switch in three dimensions. Science 294, 1299-1304
4. Repasky, G.A., Chenette, E.J., and Der, C.J. (2004) Renewing the conspiracy theory debate: does Raf function alone to mediate Ras oncogenesis? Trends Cell Biol. 14, 639-647
5. Weinstein, B. (2002) Addiction to oncogenes-the Achilles heel of cancer. Science 297, 63-64
6. Chin, L., Tam, A., Pomerantz, J., Wong, M., Holash, J., Bardeesy, N., Shen, Q., O'Hagan, R., Pantginis, J., Zhou, H., Horner, J.W. 2nd., Cordon-Cardo, C., Yancopoulos, G.D., and DePinho, R.A. (1999) Essential role for oncogenic Ras in tumour maintenance. Nature 400, 468-472
7. Podsypanina, K., Politi, K., Beverly, L.J., and Varmus, H.E. (2008) Oncogene cooperation in tumor maintenance and tumor recurrence in mouse mammary tumors induced by Myc and mutant Kras. Proc. Natl. Acad. Sci. USA 105, 5242-5247
8. de Vos, A.M., Tong, L., Milburn, M.V., Matias, P.M., Jancarik, J., Noguchi, S., Nishimura, S., Miura, K., Ohtsuka, E., and Kim, S.H. (1988) Three-dimensional structure of an oncogene protein: catalytic domain of human c-H-ras p21. Science 239, 888-893
9. Pai, E.F., Kabsch, W., Krengel, U., Holmes, K.C., John, J., and Wittinghofer, A. (1989) Structure of the guaninenucleotide- binding domain of the Ha-ras oncogene product p21 in the triphosphate conformation. Nature 341, 209-214
10. Milburn, M.V., Tong, L., deVos, A.M., Brünger, A., Yamaizumi, Z., Nishimura, S., and Kim, S.H. (1990) Molecular switch for signal transduction: structural differences between active and inactive forms of protooncogenic ras proteins. Science 247, 939-945
11. Boriack-Sjodin, P.A., Margarit, S.M., Bar-Sagi, D., and Kuriyan, J. (1998) The structural basis of the activation of Ras by Sos. Nature 394, 337-343
12. Scheffzek, K., Ahmadian, M.R., Kabsch, W., Wiesmüller, L., Lautwein, A., Schmitz, F., and Wittinghofer, A. (1997) The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science 277, 333-338
13. Pai, E.F., Krengel, U., Petsko, G.A., Goody, R.S., Kabsch, W., and Wittinghofer, A. (1990) Refined crystal structure of the triphosphate conformation of H-ras p21 at 1.35 A resolution: implications for the mechanism of GTP hydrolysis. EMBO J. 9, 2351-2359
14. Nassar, N., Horn, G., Herrmann, C., Scherer, A., McCormick, F., and Wittinghofer, A. (1995) The 2.2 Å crystal structure of the Ras-binding domain of the serine/ threonine kinase c-Raf1 in complex with Rap1A and a GTP analogue. Nature 375, 554-560
15. Pacold, M.E., Suire, S., Perisic, O., Lara-Gonzalez, S., Davis, C.T., Walker, E.H., Hawkins, P.T., Stephens, L., Eccleston, J.F., and Williams, R.L. (2000) Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase-. Cell 103, 931-943
16. Huang, L., Hofer, F., Martin, G.S., and Kim, S.H. (1998) Structural basis for the interaction of Ras with RalGDS. Nat. Struct. Biol. 5, 422-426
17. Geyer, M., Schweins, T., Herrmann, C., Prisner, T., Wittinghofer, A., and Kalbitzer, H.R. (1996) Conformational transitions in p21ras and in its complexes with the effector protein Raf-RBD and the GTPase activating protein GAP. Biochemistry 35, 10308-10320
18. Spoerner, M., Hozsa, C., Poetzl, J.A., Reiss, K., Ganser, P., Geyer, M., and Kalbitzer, H.R. (2010) Conformational states of human rat sarcoma (Ras) protein complexed with its natural ligand GTP and their role for effector interaction and GTP hydrolysis. J. Biol. Chem. 285, 39768-39778
19. Spoerner, M., Nuehs, A., Herrmann, C., Steiner, G., and Kalbitzer, H.R. (2007) Slow conformational dynamics of the guanine nucleotide-binding protein Ras complexed with the GTP analogue GTP-S. FEBS J. 274, 1419-1433
20. Liao, J., Shima, F., Araki, M., Ye, M., Muraoka, S., Sugimoto, T., Kawamura, M., Yamamoto, N., Tamura, A., and Kataoka, T. (2008) Two conformational states of Ras GTPase exhibit differential GTPbinding kinetics. Biochem. Biophys. Res. Commun. 369, 327-332
21. Spoerner, M., Herrmann, C., Vetter, I.R., Kalbitzer, H.R., and Wittinghofer, A. (2001) Dynamic properties of the Ras switch I region and its importance for binding to effectors. Proc. Natl. Acad. Sci. USA 98, 4944-4949
22. Ford, B., Skowronek, K., Boykevisch, S., Bar-Sagi, D., and Nassar, N. (2005) Structure of the G60A mutant of Ras: implications for the dominant negative effect. J. Biol. Chem. 280, 25697-25705
23. Ye, M., Shima, F., Muraoka, S., Liao, J., Okamoto, H., Yamamoto, M., Tamura, A., Yagi, N., Ueki, T., and Kataoka T. (2005) Crystal structure of M-Ras reveals a GTP-bound "off" state conformation of Ras family small GTPases. J. Biol. Chem. 280, 31267-31275
24. Shima, F., Ijiri, Y., Muraoka, S., Liao, J., Ye, M., Araki, M., Matsumoto, K., Yamamoto, N., Sugimoto, T., Yoshikawa, Y., Kumasaka, T., Yamamoto, M., Tamura, A., and Kataoka, T. (2010) Structural basis for conformational dynamics of GTP-bound Ras protein. J. Biol. Chem. 285, 22696-22705
25. Matsumoto, K., Shima, F., Muraoka, S., Araki, M., Hu, L., Ijiri, Y., Hirai, R., Liao, J., Yoshioka, T., Kumasaka, T., Yamamoto, M., Tamura, A., and Kataoka, T. (2011) Critical roles of interactions among switch I-preceding residues and between switch II and its neighboring ahelix in conformational dynamics of the GTP-bound Ras family small GTPases. J. Biol. Chem. 286, 15403-15412
26. Araki, M., Shima, F., Yoshikawa, Y., Muraoka, S., Ijiri, Y., Nagahara, Y., Shirono, T., Kataoka, T., and Tamura, A. (2011) Solution structure of the state 1 conformer of GTP-bound H-Ras protein and distinct dynamic properties between the state 1 and state 2 conformers. J. Biol. Chem. 286, 39644-39653
27. Ye, M., Shima, F., Muraoka, S., Liao, J., Okamoto, H., Yamamoto, M., Tamura, A., Yagi, N., Ueki, T., and Kataoka, T. (2005) Crystal structure of M-Ras reveals a GTP-bound "off" state conformation of Ras family small GTPases. J. Biol. Chem. 280, 31267-31275
28. Karnoub, A.E. and Weinberg, R.A. (2008) Ras oncogenes: split personalities. Nat. Rev. Mol. Cell. Biol. 9, 517-531
29. Prior, I.A., Lewis, P.D., and Mattos, C. (2012) A comprehensive survey of Ras mutations in cancer. Cancer Res. 72, 2457-2467
30. Shima, F. and Kataoka, T. (2005) Critical role of posttranslational modification of Ras proteins in effector activation. Seikagaku 77, 519-526
31. Cox, A.D. and Der, C.J. (2002) Ras family signaling: therapeutic targeting. Cancer Biol. Ther. 1, 599-606
32. Whyte, D.B., Kirschmeier, P., Hockenberry, T.N., Nunez-Oliva, I., James, L., Catino, J.J., Bishop, W.R., and Pai, J.K. (1997) K-and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. J. Biol. Chem. 272, 14459-14464
33. Wang, Y., Kaiser, C.E., Frett, B., and Li, H.Y. (2013) Targeting mutant KRAS for anticancer therapeutics: a review of novel small molecule modulators. J. Med. Chem. 56, 5219-5230
34. Berndt, N., Hamilton, A.D., and Sebti, S.M. (2011) Targeting protein prenylation for cancer therapy. Nat. Rev. Cancer 11, 775-791
35. Baines, A.T., Xu, D., and Der, C.J. (2011) Inhibition of Ras for cancer treatment: the search continues. Future Med. Chem. 3, 1787-1808
36. Dekker, F.J., Rocks, O., Vartak, N., Menninger, S., Hedberg, C., Balamurugan, R., Wetzel, S., Renner, S., Gerauer, M., Schölermann, B., Rusch, M., Kramer, J.W., Rauh, D., Coates, G.W., Brunsveld, L., Bastiaens, P.I., and Waldmann, H. (2010) Small-molecule inhibition of APT1 affects Ras localization and signaling. Nat. Chem. Biol. 6, 449-456
37. Riely, G.J., Johnson, M.L., Medina, C., Rizvi, N.A., Miller, V.A., Kris, M.G., Pietanza, M.C., Azzoli, C.G., Krug, L.M., Pao, W., and Ginsberg, M.S. (2011) A phase II trial of salirasib in patients with lung adenocarcinomas with KRAS mutations. J. Thorac. Oncol. 6, 1435-1437
38. Laheru, D., Shah, P., Rajeshkumar, N.V., McAllister, F., Taylor, G., Goldsweig, H., Le, D.T., Donehower, R., Jimeno, A., Linden, S., Zhao, M., Song, D., Rudek, M.A., and Hidalgo, M. (2012) Integrated preclinical and clininal development of S-trans, trans-farnesylthiosalicylic acid (FTS, Salirasib)in pancreatic cancer. Invest. New Drugs 30, 2391-2399
39. Zimmermann, G., Papke, B., Ismail, S., Vartak, N., Chandra, A., Hoffmann, M., Hahn, S.A., Triola, G., Wittinghofer, A., Bastiaens, P.I., and Waldmann, H. (2013). Small-molecule inhibition of KRAS-PDEd interaction impairs oncogenic KRAS signalling. Nature 497, 638-642
40. Chandra, A., Grecco, H.E., Pisupati, V., Perera, D., Cassidy, L., Skoulidis, F., Ismail, S.A., Hedberg, C., Hanzal-Bayer, M., Venkitaraman, A.R., Wittinghofer, A., and Bastiaens, P.I. (2012) The GDI-like solubilizing factor PDEd sustains the spatial organization and signalling of Ras family proteins. Nat. Cell biol. 14, 148-158
41. Lim, K.H., Ancrile, B.B., Kashatus, D.F., and Counter, C.M. (2008) Tumor maintenance is mediated by eNOS. Nature 452, 646-649
42. Maurer, T., Garrenton, L.S., Oh, A., Pitts, K., Anderson, D.J., Skelton, N.J., Fauber, B.P., Pan, B., Malek, S., Stokoe, D., Ludlam, M.J., Bowman, K.K., Wu, J., Giannetti, A.M., Starovasnik, M.A., Mellman, I., Jackson, P.K., Rudolph, J., Wang, W., and Fang, G. (2012) Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity. Proc. Natl. Acad. Sci. USA 109, 5299-5304
43. Lim, S.M., Westover, K.D., Ficarro, S.B., Harrison, R.A., Choi, H.G., Pacold, M.E., Carrasco, M., Hunter, J., Kim, N.D., Xie, T., Sim, T., Jänne, P.A., Meyerson, M., Marto, J.A., Engen, J.R., and Gray, N.S. (2014) Therapeutic targeting of oncogenic K-Ras by a covalent catalytic site inhibitor. Angew. Chem. Int. Ed. Engl. 53, 199-204
44. Ostrem, J.M., Peters, U., Sos, M.L., Wells, J.A., and Shokat, K.M. (2013) K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503, 548-551
45. Patgiri, A., Yadav, K.K., Arora, P.S., and Bar-Sagi, D. (2011) An orthosteric inhinitor of the Ras-SOS interaction. Nat. Chem. Biol. 7, 585-587
46. Müller, O., Gourzoulidou, E., Carpintero, M., Karaguni, I.M., Langerak, A., Herrmann, C., Möröy, T., Klein- Hitpass, L., and Waldmann, H. (2004) Identification of potent Ras signaling inhibitors by pathway-selective phenotype-based screening. Angew. Chem. Int. Ed. Engl. 43, 450-454
47. Waldmann, H., Karaguni, I.M., Carpintero, M., Gourzoulidou, E., Herrmann, C., Brockmann, C., Oschkinat, H., and Müller, O. (2004) Sulindac-derived Ras pathway inhibitors target the Ras-Raf interaction and downstream effectors in the Ras pathway. Angew. Chem. Int. Ed. Engl. 43, 454-458
48. González-Péez, V., Reiner, D.J., Alan, J.K., Mitchell, C., Edwards, L.J., Khazak, V., Der, C.J., and Cox, A.D. (2010) Genetic and functional characterization of putative Ras/Raf interaction inhibitors in C. elegans and mammalian cells. J. Mol. Signal. 5, 2
49. Campbell, P.M., Boufaied, N., Fiordalisi, J.J., Cox, A.D., Falardeau, P., Der, C.J., and Gourdeau, H. (2010) TLN-4601 suppresses growth and induces apoptosis of pancreatic carcinoma cells through inhibition of Ras-ERK MAPK signaling. J. Mol. Signal. 5, 18
50. Hedberg, C., Dekker, F.J., Rusch, M., Renner, S., Wetzel, S., Vartak, N., Gerding-Reimers, C., Bon, R.S., Bastiaens, P.I., and Waldmann, H. (2011) Development of highly potent inhibitors of the Ras-targeting human acyl protein thioesterases based on substrate similarity design. Angew. Chem. Int. Ed. Engl. 50, 9832-9837
51. Winter-Vann, A.M., Baron, R.A., Wong, W., dela Cruz, J., York, J.D., Gooden, D.M., Bergo, M.O., Young, S.G., Toone, E.J., and Casey, P.J. (2005) A small-molecule inhibitor of isoprenylcysteine carboxyl methyltransferase with antitumor activity in cancer cells. Proc. Natl. Acad. Sci. USA 102, 4336-4341
52. Ganguly, A.K., Wang, Y.S., Pramanik, B.N., Doll, R.J., Snow, M.E., Taveras, A.G., Remiszewski, S., Cesarz, D., del Rosario, J., Vibulbhan, B., Brown, J.E., Kirschmeier, P., Huang, E.C., Heimark, L., Tsarbopoulos, A., Girijavallabhan, V.M., Aust, R.M., Brown, E.L., DeLisle, D.M., Fuhrman, S.A., Hendrickson, T.F., Kissinger, C.R., Love, R.A., Sisson, W.A., Villafranca, J.E., and Webber, S.E. (1998) Interaction of a novel GDP exchange inhibitor with the Ras protein. Biochemistry 37, 15631-15637
53. Taveras, A.G., Remiszewski, S.W., Doll, R.J., Cesarz, D., Huang, E.C., Kirschmeier, P., Pramanik, B.N., Snow, M.E., Wang, Y.S., del Rosario, J.D., Vibulbhan, B., Bauer, B.B., Brown, J.E., Carr, D., Catino, J., Evans, C.A., Girijavallabhan, V., Heimark, L., James, L., Liberles, S., Nash, C., Perkins, L., Senior, M.M., Tsarbopoulos, A., Gangulya, A.K., Austb, R., Brownb, E., Delisleb, D., Fuhrmanb, S., Hendricksonb, T., Kissingerb, C., Loveb, R., Sissonb, W., Villafrancab, E., and Webber, S.E. (1997) Ras oncoprotein inhibitors: the discovery of potent, ras nucleotide exchange inhibitors and the structural determination of a drugprotein complex. Bioorg. Med. Chem. 5, 125-133
54. Hocker, H.J., Cho, K.J., Chen, C.Y., Rambahal, N., Sagineedu, S.R., Shaari, K., Stanslas, J., Hancock, J.F., and Gorfe, A.A. (2013) Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function. Proc. Natl. Acad. Sci. USA 110, 10201-10206
55. Sun, Q., Burke, J.P., Phan, J., Burns, M.C., Olejniczak, E.T., Waterson, A.G., Lee, T., Rossanese, O.W., and Fesik, S.W. (2012) Discovery of small molecules that bind to K-Ras and inhibit Sos-mediated activation. Angew. Chem. Int. Ed. Engl. 51, 6140-6143
56. Schöpel, M., Jockers, K.F., Düppe, P.M., Autzen, J., Potheraveedu, V.N., Ince, S., Yip, K.T., Heumann, R., Herrmann, C., Scherkenbeck, J., and Stoll, R. (2013) Bisphenol A binds to Ras proteins and competes with guanine nucleotide exchange: implications for GTPaseselective antagonists. J. Med. Chem. 56, 9664-9672
57. Spoerner, M., Graf, T., König, B., and Kalbitzer, H.R. (2005) A novel mechanism for the modulation of the Ras-effector interaction by small molecules. Biochem. Biophys. Res. Commun. 334, 709-713
58. Rosnizeck, I.C., Graf, T., Spoerner, M., Tränkle, J., Filchtinski, D., Herrmann, C., Gremer, L., Vetter, I.R., Wittinghofer, A., König, B., and Kalbitzer, H.R. (2010) Stabilizing a weak binding state for effectors in the human Ras protein by cyclen complexes. Angew. Chem. Int. Ed. Engl. 49, 3830-3833
59. Rosnizeck, I.C., Spoerner, M., Harsch, T., Kreitner, S., Filchtinski, D., Herrmann, C., Engel, D., König, B., and Kalbitzer, H.R. (2012) Metal-bis(2-picolyl)amine complexes as state 1(T) inhibitors of activated Ras protein. Angew. Chem. Int. Ed. Engl. 51, 10647-10651
60. Tanaka, T., Williams, R.L., and Rabbitts, T.H. (2007) Tumour prevention by a single antibody domain targeting the interaction of signal transduction proteins with RAS. EMBO J. 26, 3250-3259
61. Pasricha, P.J., Bedi, A., O'Connor, K., Rashid, A., Akhtar, A.J., Zahurak, M.L., Piantadosi, S., Hamilton, S.R., and Giardiello, F.M. (1995) The effects of sulindac on colorectal proliferation and apoptosis in familial adenomatous polyposis. Gastroenterology 109, 994-998
62. Shima, F., Yoshikawa, Y., Ye, M., Araki, M., Matsumoto, S., Liao, J., Hu, L., Sugimoto, T., Ijiri, Y., Takeda, A., Nishiyama, Y., Sato, C., Muraoka, S., Tamura, A., Osoda, T., Tsuda, K., Miyakawa, T., Fukunishi, H., Shimada, J., Kumasaka, T., Yamamoto, M., and Kataoka, T. (2013) In silico discovery of smallmolecule Ras inhibitors that display antitumor activity by blocking the Ras-effector interaction. Proc. Natl. Acad. Sci. USA 110, 8182-8187