OJBIPHY  Vol.3 No.4 , October 2013
Prospective Development of Small Molecule Targets to Oncogenic Ras Proteins

Abnormal expression or mutations in Ras proteins has been found in up to 30% of cancer cell types, making them excellent protein models to probe structure-function relationships of cell-signaling processes that mediate cell transformtion. Yet, there has been very little development of therapies to help tackle Ras-related diseased states. The development of small molecules to target Ras proteins to potentially inhibit abnormal Ras-stimulated cell signaling has been conceptualized and some progress has been made over the last 16 or so years. Here, we briefly review studies characterizing Ras protein-small molecule interactions to show the importance and potential that these small molecules may have for Ras-related drug discovery. We summarize recent results, highlighting small molecules that can be directly targeted to Ras using Structure-Based Drug Design (SBDD) and Fragment-Based Lead Discovery (FBLD) methods. The inactivation of Ras oncogenic signaling in vitro by small molecules is currently an attractive hurdle to try to and leap over in order to attack the oncogenic state. In this regard, important features of previously characterized properties of small molecule Ras targets, as well as a current understanding of conformational and dynamics changes seen for Ras-related mutants, relative to wild type, must be taken into account as newer small molecule design strategies towards Ras are developed.

Cite this paper: Chandrashekar, R. and Adams, P. (2013) Prospective Development of Small Molecule Targets to Oncogenic Ras Proteins. Open Journal of Biophysics, 3, 207-211. doi: 10.4236/ojbiphy.2013.34025.

[1]   J. L. Bos, “Ras Oncogenes in Human Cancer: A Review,” Cancer Research, Vol. 49, No. 17, 1989, pp. 4682-4689.

[2]   A. T. Baines, D. Xu and C. J. Der, “Inhibition of Ras for Cancer Treatment: The Search Continues,” Future Medicinal Chemistry, Vol. 3, No. 14, 2011, pp. 1787-1808.

[3]   S. Gysin, M. Salt, A. Young and F. McCormick, “Therapeutic strategies for Targeting Ras Proteins,” Genes & Cancer, Vol. 2, No. 3, 2011, pp. 359-372.

[4]   W. Guo, M. J. Sutcliffe, R. A. Cerione and R. E. Oswald, “Identification of the Binding Surface on Cdc42Hs for p21-Activated Kinase,” Biochemistry, Vol. 37, No. 40, 1998, pp. 14030-14037.

[5]   P. D. Adams, A. P. Loh and R. E. Oswald, “Backbone Dynamics of an Oncogenic Mutant of Cdc42Hs Shows Increased Flexibility at the Nucleotide-Binding Site,” Biochemistry, Vol. 43, No. 31, 2004, pp. 9968-9977.

[6]   R. Lin, S. Bagrodia, R. Cerione and D. Manor, “A Novel Cdc42Hs Mutant Induces Cellular Transformation,” Current Biology, Vol. 7, No. 10, 1997, pp. 794-797.

[7]   A. G. Taveras, S. W. Remiszewski, R. J. Doll, D. Cesarz, E. C. Huang, P. Kirschmeier, B. N. Pramanik, M. E. Snow, Y. S. Wang, J. D. del Rosario, B. Vibulbhan, B. B. Bauer, J. E. Brown, D. Carr, J. Catino, C. A. Evans, V. Girijavallabhan, L. Heimark, L. James, S. Liberles, C. Nash, L. Perkins, M. M. Senior, A. Tsarbopoulos, S. E. Webber, et al., “Ras Oncoprotein Inhibitors: The Discovery of Potent, Ras Nucleotide Exchange Inhibitors and the Structural Determination of a Drug-Protein Complex,” Bioorganic & Medicinal Chemistry, Vol. 5, No. 1, 1997, pp. 125-133.

[8]   M. R. Ahmadian, T. Zor, D. Vogt, W. Kabsch, Z. Selinger, A. Wittinghofer and K. Scheffzek, “Guanosine Triphosphatase Stimulation of Oncogenic Ras Mutants,” Proceedings of the National Academy Sciences of the USA, Vol. 96, No. 12, 1999, pp. 7065-7070.

[9]   A. Palmioli, E. Sacco, S. Abraham, C. J. Thomas, A. Di Domizio, L. De Gioia, V. Gaponenko, M. Vanoni and F. Peri, “First Experimental Identification of Ras-Inhibitor Binding Interface Using a Water-Soluble Ras Ligand,” Bioorganic & Medicinal Chemistry Letters, Vol. 19, No. 15, 2009, pp. 4217-4222.

[10]   H. Waldmann, I. M. Karaguni, M. Carpintero, E. Gourzoulidou, C. Herrmann, C. Brockmann, H. Oschkinat and O. Muller, “Sulindac-Derived Ras Pathway Inhibitors Target the Ras-Raf Interaction and Downstream Effectors in the Ras Pathway,” Angewandte Chemie International Edition, Vol. 43, No. 4, 2004, pp. 454-458.

[11]   J. Kato-Stankiewicz, I. Hakimi, G. Zhi, J. Zhang, I. Serebriiskii, L. Guo, H. Edamatsu, H. Koide, S. Menon, R. Eckl, S. Sakamuri, Y. Lu, Q. Z. Chen, S. Agarwal, W. R. Baumbach, E. A. Golemis, F. Tamanoi and V. Khazak, “Inhibitors of Ras/Raf-1 Interaction Identified by Two Hybrid Screening Revert Ras-Dependent Transformation Phenotypes in Human Cancer Cells,” Proceedings of the National Academy Sciences of the USA, Vol. 99, No. 22, 2002, pp. 14398-14403.

[12]   V. Gonzalez-Perez, D. J. Reiner, J. K. Alan, C. Mitchell, L. J. Edwards, V. Khazak, C. J. Der and A. D. Cox, “Genetic and Functional Characterization of Putative Ras/Raf Interaction Inhibitors in C. elegans and Mammalian Cells,” Journal of Molecular Signaling, Vol. 5, No. 1, 2010, p. 2.

[13]   I. C. Rosnizeck, T. Graf, M. Spoerner, J. Trankle, D. Filchtinski, C. Herrmann, L. Gremer, I. R. Vetter, A. Wittinghofer, B. Konig and H. R. Kalbitzer, “Stabilizing a Weak Binding State for Effectors in the Human Ras Protein by Cyclen Complexes,” Angewandte Chemie International Edition, Vol. 49, No. 22, 2010, pp. 3830-3833.

[14]   W. Wang, G. Fang and J. Rudolph, “Ras Inhibition via Direct Ras Binding—Is There a Path Forward?” Bioorganic & Medicinal Chemistry Letters, Vol. 22, No. 18, 2012, pp. 5766-5776.

[15]   D. E. Scott, A. G. Coyne, S. A. Hudson and C. Abell, “Fragment-Based Approaches in Drug Discovery and Chemical Biology,” Biochemistry, Vol. 51, No. 25, 2012, pp. 4990-5003.

[16]   D. E. Scott, M. T. Ehebauer, T. Pukala, M. Marsh, T. L. Blundell, A. R. Venkitaraman, C. Abell and M. Hyvonen, “Using a Fragment-Based Approach to Target Protein- Protein Interactions,” ChemBioChem, Vol. 14, No. 3, 2013, pp. 332-342.

[17]   R. Chandrashekar, O. Salem, H. Krizova, R. McFeeters and P. D. Adams, “A Switch I Mutant of Cdc42 Exhibits Less Conformational Freedom,” Biochemistry, Vol. 50, No. 28, 2011, pp. 6196-6207.

[18]   M. Baker, “Fragment-Based Lead Discovery Grows Up,” Nature Reviews and Drug Discovery, Vol. 12, No. 1, 2013, pp. 5-7.

[19]   R. A. Carr, M. Congreve, C. W. Murray and D. C. Rees, “Fragment-Based Lead Discovery: Leads by Design,” Drug Discovery Today, Vol. 10, No. 14, 2005, pp. 987-992.

[20]   T. Maurer, L. S. Garrenton, A. Oh, K. Pitts, D. J. Anderson, N. J. Skelton, B. P. Fauber, B. Pan, S. Malek, D. Stokoe, M. J. Ludlam, K. K. Bowman, J. Wu, A. M. Giannetti, M. A. Starovasnik, I. Mellman, P. K. Jackson, J. Rudolph, W. Wang and G. Fang, “Small-Molecule Ligands Bind to a Distinct Pocket in Ras and Inhibit SOS-Mediated Nucleotide Exchange Activity,” Proceedings of the National Academy Sciences of the USA, Vol. 109, No. 14, 2012, pp. 5299-5304.

[21]   A. Friesland, Y. Zhao, Y. H. Chen, L. Wang, H. Zhou and Q. Lu, “Small Molecule Targeting Cdc42-Intersectin Interaction Disrupts Golgi Organization and Suppresses Cell Motility,” Proceedings of the National Academy Sciences of the USA, Vol. 110, No. 4, 2013, pp. 1261-1266.

[22]   S. Muraoka, F. Shima, M. Araki, T. Inoue, A. Yoshimoto, Y. Ijiri, N. Seki, A. Tamura, T. Kumasaka, M. Yamamoto and T. Kataoka, “Crystal Structures of the State 1 Conformations of the GTP-Bound H-Ras Protein and Its Oncogenic G12V and Q61L Mutants,” FEBS Letters, Vol. 586, No.12, 2012, pp. 1715-1718.

[23]   F. Shima, Y. Ijiri, S. Muraoka, J. Liao, M. Ye, M. Araki, K. Matsumoto, N. Yamamoto, T. Sugimoto, Y. Yoshikawa, T. Kumasaka, M. Yamamoto, A. Tamura and T. Kataoka, “Structural Basis for Conformational Dynamics of GTP- Bound Ras Protein,” Journal of Biological Chemistry, Vol. 285, 2010, pp. 22696-22705.

[24]   M. Ye, F. Shima, S. Muraoka, J. Liao, H. Okamoto, M. Yamamoto, A. Tamura, N. Yagi, T. Ueki and T. Kataoka, “Crystal Structure of M-Ras Reveals a GTP-Bound ‘Off’ State Conformation of Ras Family Small GTPases,” Journal of Biological Chemistry, Vol. 280, 2005, pp. 31267- 31275.

[25]   F. Shima, Y. Yoshikawa, M. Ye, M. Araki, S. Matsumoto, J. Liao, L. Hu, T. Sugimoto, Y. Ijiri, A. Takeda, Y. Nishiyama, C. Sato, S. Muraoka, A. Tamura, T. Osoda, K. Tsuda, T. Miyakawa, H. Fukunishi, J. Shimada, T. Kumasaka, M. Yamamoto and T. Kataoka, “In Silico Discovery of Small-Molecule Ras Inhibitors that Display Antitumor Activity by Blocking the Ras-Effector Interaction,” Proceedings of the National Academy Sciences of the USA, Vol. 110, No. 20, 2013, pp. 8182-8187.