In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras-effector interaction

Proceedings of the National Academy of Sciences of the United States of America

Volumn 110, Issue 20, 2013, Pages 8182-8187

  Shima, Fumi ^a   Yoshikawa, Yoko ^a   Ye, Min ^a   Araki, Mitsugu ^a,b   Matsumoto, Shigeyuki ^a   Liao, Jingling ^a   Hu, Lizhi ^a   Sugimoto, Takeshi ^a   Ijiri, Yuichi ^a   Takeda, Azusa ^a   Nishiyama, Yuko ^a   Sato, Chie ^a   Muraoka, Shin ^a   Tamura, Atsuo ^b   Osoda, Tsutomu ^c   Tsuda, Ken Ichiro ^c   Miyakawa, Tomoya ^c   Fukunishi, Hiroaki ^d   Shimada, Jiro ^d   Kumasaka, Takashi ^e   Yamamoto, Masaki ^e   Kataoka, Tohru ^a   more..

^a KOBE UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

^b KOBE UNIVERSITY   (Japan)

^c NEC CORPORATION   (Japan)

^d JAPAN SYNCHROTRON RADIATION RESEARCH INSTITUTE   (Japan)

^e RIKEN SPring 8 Center ^*  (Japan)

Author keywords

Molecular targeted therapy; Small molecule inhibitor

Indexed keywords

ANTINEOPLASTIC AGENT; GUANOSINE TRIPHOSPHATE; K RAS PROTEIN; KOBE 0065; KOBE 2602; PROTEIN KINASE B; RAF PROTEIN; RAS PROTEIN; UNCLASSIFIED DRUG;

ANCHORAGE INDEPENDENT GROWTH; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ARTICLE; BINDING AFFINITY; CELL STRAIN 3T3; COLON CARCINOMA; COMPUTER MODEL; CRYSTAL STRUCTURE; DOWN REGULATION; DRUG DESIGN; DRUG POTENCY; DRUG SPECIFICITY; ENZYME ACTIVITY; GENE OVEREXPRESSION; HUMAN; HUMAN CELL; HUMAN TISSUE; IC 50; IN VITRO STUDY; IN VIVO STUDY; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN CONFORMATION; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; PROTEIN TARGETING; TUMOR XENOGRAFT;

MOLECULAR TARGETED THERAPY; SMALL-MOLECULE INHIBITOR;

ANIMALS; ANTINEOPLASTIC AGENTS; CELL LINE, TRANSFORMED; CELL LINE, TUMOR; COMPUTATIONAL BIOLOGY; DRUG DESIGN; GLUTATHIONE TRANSFERASE; GUANOSINE TRIPHOSPHATE; HUMANS; MICE; MICE, NUDE; MODELS, MOLECULAR; MOLECULAR CONFORMATION; MUTATION; NEOPLASM TRANSPLANTATION; NIH 3T3 CELLS; PROTEIN BINDING; PROTEIN CONFORMATION; RAS PROTEINS; SIGNAL TRANSDUCTION;

EID: 84877863454     PISSN: 00278424     EISSN: 10916490     Source Type: Journal    
DOI: 10.1073/pnas.1217730110     Document Type: Article

References (27)

1. Karnoub AE, Weinberg RA (2008) Ras oncogenes: Split personalities. Nat Rev Mol Cell Biol 9(7):517-531. (Pubitemid 351881844)
2. Vetter IR, Wittinghofer A (2001) The guanine nucleotide-binding switch in three dimensions. Science 294(5545):1299-1304. (Pubitemid 33063089)
3. Weinstein IB (2002) Cancer. Addiction to oncogenes-The Achilles heal of cancer. Science 297(5578):63-64. (Pubitemid 34743088)
4. Chin L, et al. (1999) Essential role for oncogenic Ras in tumour maintenance. Nature 400(6743):468-472. (Pubitemid 29361802)
5. Podsypanina K, Politi K, Beverly LJ, Varmus HE (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(13):5242-5247. (Pubitemid 351738541)
6. James GL, Goldstein JL, Brown MS (1995) Polylysine and CVIM sequences of K-RasB dictate specificity of prenylation and confer resistance to benzodiazepine peptidomimetic in vitro. J Biol Chem 270(11):6221-6226.
7. Rotblat B, Ehrlich M, Haklai R, Kloog Y (2008) The Ras inhibitor farnesylthiosalicylic acid (Salirasib) disrupts the spatiotemporal localization of active Ras: A potential treatment for cancer. Methods Enzymol 439:467-489.
8. Ye M, et al. (2005) Crystal structure of M-Ras reveals a GTP-bound "off" state conformation of Ras family small GTPases. J Biol Chem 280(35):31267-31275. (Pubitemid 41291864)
9. Shima F, et al. (2010) Structural basis for conformational dynamics of GTP-bound Ras protein. J Biol Chem 285(29):22696-22705.
10. Muraoka S, et al. (2012) Crystal structures of the state 1 conformations of the GTPbound H-Ras protein and its oncogenic G12V and Q61L mutants. FEBS Lett 586(12): 1715-1718.
11. Wilhelm S, et al. (2006) Discovery and development of sorafenib: A multikinase inhibitor for treating cancer. Nat Rev Drug Discov 5(10):835-844. (Pubitemid 44480537)
12. Margarit SM, et al. (2003) Structural evidence for feedback activation by Ras.GTP of the Ras-specific nucleotide exchange factor SOS. Cell 112(5):685-695. (Pubitemid 36331780)
13. Araki M, et al. (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(45):39644-39653.
14. Ito Y, et al. (1997) Regional polysterism in the GTP-bound form of the human c-Ha-Ras protein. Biochemistry 36(30):9109-9119. (Pubitemid 27329495)
15. Nassar N, et al. (1995) The 2.2 A crystal structure of the Ras-binding domain of the serine/threonine kinase c-Raf1 in complex with Rap1A and a GTP analogue. Nature 375(6532):554-560.
16. Pacold ME, et al. (2000) Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase gamma. Cell 103(6):931-943.
17. Huang L, Hofer F, Martin GS, Kim SH (1998) Structural basis for the interaction of Ras with RalGDS. Nat Struct Biol 5(6):422-426. (Pubitemid 28265022)
18. Hajduk PJ, Olejniczak ET, Fesik SW (1997) One-dimensional relaxation-and diffusionedited NMR methods for screening compounds that bind to macromolecules. J Am Chem Soc 119:12257-12261. (Pubitemid 28078713)
19. Maurer T, et al. (2012) Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity. Proc Natl Acad Sci USA 109(14): 5299-5304.
20. Sun Q, et al. (2012) Discovery of small molecules that bind to K-Ras and inhibit Sosmediated activation. Angew Chem Int Ed Engl 51(25):6140-6143.
21. Lim KH, Ancrile BB, Kashatus DF, Counter CM (2008) Tumour maintenance is mediated by eNOS. Nature 452(7187):646-649. (Pubitemid 351483359)
22. Sitkoff D, Sharp KA, Honig B (1994) Accurate calculation of hydration free energies using macroscopic solvent models. J Phys Chem 98:1978-1988.
23. Fukunishi Y, Mikami Y, Nakamura H (2003) The filing potential method: A method for estimating the free energy surface for protein-ligand docking. J Phys Chem B 107: 13201-13210.
24. Fukunishi Y, Mikami Y, Nakamura H (2005) Similarities among receptor pockets and among compounds: Analysis and application to in silico ligand screening. J Mol Graph Model 24(1):34-45. (Pubitemid 41318116)
25. Carhart RE, Smith DH, Venkataraghavan R (1985) Atom pairs as molecular features in structure-activity studies: Defenition and applications. J Chem Inf Comput Sci 25: 64-73.
26. Willett P, Barnard JM, Downs GM (1998) Chemical similarity searching. J Chem Inf Comput Sci 38:983-996. (Pubitemid 128591261)
27. Koradi R, Billeter M, Wuthrich K (1996) MOLMOL: A program for display and analysis of macromolecular structures. J Mol Graph 14(1):51-55. (Pubitemid 26152976)