CIGB-300, a synthetic peptide-based drug that targets the CK2 phosphoaceptor domain. Translational and clinical research.

Abstract

CK2 represents an oncology target scientifically validated. However, clinical research with inhibitors of the CK2-mediated phosphorylation event is still insufficient to recognize it as a clinically validated target. CIGB-300, an investigational peptide-based drug that targets the phosphoaceptor site, binds to a CK2 substrate array in vitro but mainly to B23/nucleophosmin in vivo. The CIGB-300 proapoptotic effect is preceded by its nucleolar localization, inhibition of the CK2-mediated phosphorylation on B23/nucleophosmin and nucleolar disassembly. Importantly, CIGB-300 shifted a protein array linked to apoptosis, ribosome biogenesis, cell proliferation, glycolisis, and cell motility in proteomic studies which helped to understand its mechanism of action. In the clinical ground, CIGB-300 has proved to be safe and well tolerated in a First-in-Human trial in women with cervical malignancies who also experienced signs of clinical benefit. In a second Phase 1 clinical trial in women with cervical cancer stage IB2/II, the MTD and DLT have been also identified in the clinical setting. Interestingly, in cervical tumors the B23/nucleophosmin protein levels were significantly reduced after CIGB-300 treatment at the nucleus compartment. In addition, expanded use of CIGB-300 in case studies has evidenced antitumor activity when administered as compassional option. Collectively, our data outline important clues on translational and clinical research from this novel peptide-based drug reinforcing its perspectives to treat cancer and paving the way to validate CK2 as a promising target in oncology.

• Authors: Silvio E Perea, Idania Baladron, Yanelda Garcia, Yasser Perera, Adlin Lopez, Jorge L Soriano, Noyde Batista, Aley Palau, Ignacio Hernández, Hernán Farina, Idrian Garcia, Lidia Gonzalez, Jeovanis Gil, Arielis Rodriguez, Margarita Solares, Agueda Santana, Marisol Cruz, Matilde Lopez, Carmen Valenzuela, Osvaldo Reyes, Pedro A López-Saura, Carlos A González, Alina Diaz, Lila Castellanos, Aniel Sanchez, Lazaro Betancourt, Vladimir Besada, Luis J González, Hilda Garay, Roberto Gómez, Daniel E Gómez, Daniel F Alonso, Phillipe Perrin, Jean-Yves Renualt, Hugo Sigman, Luis Herrera, Boris Acevedo
• Journal: Molecular and cellular biochemistry (Mol Cell Biochem) Vol. 356 Issue 1-2 Pg. 45-50 (Oct 2011) ISSN: 1573-4919 [Electronic] Netherlands
• PMID: 21735096 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• NPM1 protein, human
• Nuclear Proteins
• Peptides, Cyclic
• Nucleophosmin
• Casein Kinase II
• CIGB-300

Topics

• Casein Kinase II (antagonists & inhibitors, chemistry, metabolism)
• Cell Line, Tumor
• Female
• Humans
• Magnetic Resonance Imaging
• Male
• Nuclear Proteins (metabolism)
• Nucleophosmin
• Peptides, Cyclic (pharmacology)
• Phosphorylation (drug effects)
• Protein Binding (drug effects)
• Protein Structure, Tertiary
• Translational Research, Biomedical