Therapeutic Approaches

Targeted Therapies with novel mechanisms are offering new and effective treatments for cancer patients and improved quality of life. Cylene is pioneering entirely new approaches to Targeted Therapies primarily through its Ribosomal RNA Biogenesis Inhibitor technology (RABIT™), as well as by taking advantage of the company's advanced chemical library for Next Generation Inhibitors.

RBI Technology

A hallmark of cancer cells is a deregulation in signaling, which results in the cancer cells' dependence on elevated rates of ribosomal RNA (rRNA) biogenesis. The elevated rate of rRNA biogenesis in cancer cells allows for rampant proliferation. Consequently, inhibition of rRNA biogenesis represents a validated approach to selective killing of cancer cells, though the majority of drugs in this class work via indirect inhibition of rRNA biogenesis by targeting upstream kinase pathways (e.g. Avastin®, Herceptin®, Gleevec®, Erbitux® and Rituxan®). Cylene’s strategy is to engineer small molecules that target the G-quadruplex:Nucleolin complexes that are amplified in cancer cells and directly inhibit rRNA biogenesis, thus introducing target novelty and a broad range of action while reducing risk.

Discovery Processes

Cylene has built a propriety screening technology that rapidly identifies molecules that selectively bind to specific secondary nucleic acid structures. Molecules are extensively characterized early in the discovery process for their ADMET and stability properties and for their capacity to selectively trigger cell signaling pathways of interest. This strategy allows the company to rapidly discover high quality molecules with favorable pharmaceutical properties, and to progress the premier molecules to the clinic.

Relevant Articles

Survey of Relevant External Publications

rRNA Biogenesis and Nucleolar Function

Russell, J. and Zomerdijk, J. C. B. M. (2005). RNA-polymerase-I-directed rDNA transcription, life and works.” Trends Biochem Sci 30(2): 87-96

White, R. (2005). "RNA Polymerases I and III, Growth Control, and Cancer." Nature Rev 6:69-78

Grummt, I. (2003). “Life on a planet of its own: regulation of RNA polymerase I transcription in the nucleolus.” Genes Dev 17: 1691-1702

Hernandez-Verdun, D. and Roussel, P. (2003). “Regulators of nucleolar functions.” Prog Cell Cycle Res 5: 301-308

Raska, I., Koberna, K., Malinski, J., Fidlerova, H., and Masata, M. (2004). “The nucleolus and transcription of ribosomal genes.” Biol Cell 96: 579-594

Jordan, P. and Carmo-Fonseca, M. (1998). “Cisplatin inhibits synthesis of ribosomal RNA in vivo.” Nucleic Acids Res 26(12): 2831-2836

Nucleolus – Abnormal in Cancer

Derenzini, M., Trere, D., Pession, A., Govoni, M., Sirri, V. and Chieco, P. (2000). “Nucleolar size indicates the rapidity of cell proliferation in cancer tissues.” J Pathol 191: 181-186

Romao-Correa, R. F., Maria, D.A., Soma, M., Soto, M. N., Sanches, J. A., Neto, C. F., Ruiz, I. R. G. (2005). “Nucleolar organizer region staining patterns in paraffin-embedded tissue cells from human skin cancers.” J Cutan Pathol 32: 323-328

Zink, D., Fischer, A. H. and Nickerson, J. A. (2004). “Nuclear Structure in Cancer Cells.” Nat Rev Cancer 4: 677-687

Quadruplex

Fischer, A. H., Bardarov, S., and Jiang, Z. (2004). “Molecular Aspects of Diagnostic Nucleolar and Nuclear Envelope Changes in Prostate Cancer.” J Cell Biochem 91: 170-184

Total synthesis of psorospermin. Schwaebe, M.K., Moran, T.J., Whitten, J.P. Tetrahedron Letters, Volume 46, Issue 5, 2005. Pages 827-829.

Marilley, M., Radebaugh, C. A., Geiss, G. K., Laybourne, P. J. and Paule, M. R. (2002). “DNA structural variation affects complex formation and promoter melting in ribosomal RNA transcription.” Mol Genet Genomics 267: 781-791

Duquette, M. L., Handa, P., Vincent, J. A., Taylor, A. F. and Maizels, N. (2004). “Intracellular transcription of G-rich DNAs induces formation of G-loops, novel structures containing G4 DNA.” Genes Dev 18: 1618-1629

Maizels, N. (2006). “Quadruplexes and the Biology of G-rich Genomic Regions.” Royal Society of Chemistry Press/Springer USA : 1-40

Nucleolin

Ginisty, H., Amalric, F. and Bouvet, P. (1998). “Nucleolin functions in the first step of ribosomal RNA processing.” EMBO J 17(5): 1476-1486

Roger, B., Moisand, A., Amalric, F. and Bouvet, P. (2002). “Repression of RNA Polymerase I Transcription by Nucleolin Is Independent of the RNA Sequence That Is Transcribed.” J Biol Chem 277(12): 10209-10219

Sengupta, T. K., Bandyopadhyay, S., Fernandes, D. J. and Spicer, E. K. (2004). “Identification of Nucleolin as an AU-rich Element Binding Protein Involved in bcl-2 mRNA Stabilization.” J Biol Chem 279(12): 10855-10863

Kamb, A. (2005). “What’s wrong with our cancer models?” Nat Rev Drug Discov 4: 161-165

Ruggero, D. and Pandolfi, P. (2003). “Does The Ribosome Translate Cancer?” Nat Rev Cancer 3: 179-192