cigb-300 has been researched along with Neoplasms* in 5 studies
1 review(s) available for cigb-300 and Neoplasms
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CIGB-300: A peptide-based drug that impairs the Protein Kinase CK2-mediated phosphorylation.
Protein kinase CK2, formerly referred to as casein kinase II, is a serine/threonine kinase often found overexpressed in solid tumors and hematologic malignancies that phosphorylates many substrates integral to the hallmarks of cancer. CK2 has emerged as a viable oncology target having been experimentally validated with different kinase inhibitors, including small molecule ATP-competitors, synthetic peptides, and antisense oligonucleotides. To date only two CK2 inhibitors, CIGB-300 and CX-4945, have entered the clinic in phase 1-2 trials. This review provides information on CIGB-300, a cell-permeable cyclic peptide that inhibits CK2-mediated phosphorylation by targeting the substrate phosphoacceptor domain. We review data that support the concept of CK2 as an anticancer target, address the mechanism of action, and summarize preclinical studies showing antiangiogenic and antimetastatic effects as well as synergism with anticancer drugs in preclinical models. We also summarize early clinical research (phase 1/2 trials) of CIGB-300 in cervical cancer, including data in combination with chemoradiotherapy. The clinical data demonstrate the safety, tolerability, and clinical effects of intratumoral injections of CIGB-300 and provide the foundation for future phase 3 clinical trials in locally advanced cervical cancer in combination with standard chemoradiotherapy. Topics: Animals; Antineoplastic Agents; Casein Kinase II; Clinical Trials as Topic; Humans; Neoplasms; Peptides, Cyclic; Phosphorylation; Protein Kinase Inhibitors; Xenograft Model Antitumor Assays | 2018 |
4 other study(ies) available for cigb-300 and Neoplasms
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Characterization of low-abundance species in the active pharmaceutical ingredient of CIGB-300: A clinical-grade anticancer synthetic peptide.
CIGB-300 is a first-in-class synthetic peptide-based drug of 25 amino acids currently undergoing clinical trials in cancer patients. It contains an amidated disulfide cyclic undecapeptide fused to the TAT cell-penetrating peptide through a beta-alanine spacer. CIGB-300 inhibits the CK2-mediated phosphorylation leading to apoptosis of tumor cells in vitro, and in vivo in cancer patients. Despite the clinical development of CIGB-300, the characterization of peptide-related impurities present in the active pharmaceutical ingredient has not been reported earlier. In the decision tree of ICHQ3A(R2) guidelines, the daily doses intake, the abundance, and the identity of the peptide-related species are pivotal nodes that define actions to be taken (reporting, identification, and qualification). For this, purity was first assessed by reverse-phase chromatography (>97%) and low-abundance impurities (≤0.27%) were collected and identified by mass spectrometry. Most of the impurities were generated during peptide synthesis, the spontaneous air oxidation of the reduced peptide, and the lyophilization step. The most abundant impurity, with no biological activity, was the full-length peptide containing Met Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell-Penetrating Peptides; Chemistry Techniques, Synthetic; Humans; Neoplasms; Peptides; Peptides, Cyclic; Phosphorylation | 2018 |
Molecular Pathways: Emergence of Protein Kinase CK2 (CSNK2) as a Potential Target to Inhibit Survival and DNA Damage Response and Repair Pathways in Cancer Cells.
Protein kinase CK2 (designated CSNK2) is a constitutively active protein kinase with a vast repertoire of putative substrates that has been implicated in several human cancers, including cancer of the breast, lung, colon, and prostate, as well as hematologic malignancies. On the basis of these observations, CSNK2 has emerged as a candidate for targeted therapy, with two CSNK2 inhibitors in ongoing clinical trials. CX-4945 is a bioavailable small-molecule ATP-competitive inhibitor targeting its active site, and CIGB-300 is a cell-permeable cyclic peptide that prevents phosphorylation of the E7 protein of HPV16 by CSNK2. In preclinical models, either of these inhibitors exhibit antitumor efficacy. Furthermore, in combinations with chemotherapeutics such as cisplatin or gemcitabine, either CX-4945 or CIGB-300 promote synergistic induction of apoptosis. While CSNK2 is a regulatory participant in many processes related to cancer, its potential to modulate caspase action may be particularly pertinent to its emergence as a therapeutic target. Because the substrate recognition motifs for CSNK2 and caspases are remarkably similar, CSNK2 can block the cleavage of many caspase substrates through the phosphorylation of sites adjacent to cleavage sites. Phosphoproteomic strategies have also revealed previously underappreciated roles for CSNK2 in the phosphorylation of several key constituents of DNA damage and DNA repair pathways. Going forward, applications of proteomic strategies to interrogate responses to CSNK2 inhibitors are expected to reveal signatures for CSNK2 inhibition and molecular insights to guide new strategies to interfere with its potential to inhibit caspase action or enhance the susceptibility of cancer cells to DNA damage. Clin Cancer Res; 22(12); 2840-7. ©2016 AACR. Topics: Adenosine Triphosphate; Antineoplastic Agents; Apoptosis; Casein Kinase II; Cell Line, Tumor; DNA Damage; DNA Repair; Humans; Naphthyridines; Neoplasms; Papillomavirus E7 Proteins; Peptides, Cyclic; Phenazines; Phosphorylation; Protein Kinase Inhibitors | 2016 |
Bio-analytical method based on MALDI-MS analysis for the quantification of CIGB-300 anti-tumor peptide in human plasma.
A fully validated bio-analytical method based on Matrix-Assisted-Laser-Desorption/Ionization-Time of Flight Mass Spectrometry was developed for quantitation in human plasma of the anti-tumor peptide CIGB-300. An analog of this peptide acetylated at the N-terminal, was used as internal standard for absolute quantitation. Acid treatment allowed efficient precipitation of plasma proteins as well as high recovery (approximately 80%) of the intact peptide. No other chromatographic step was required for sample processing before MALDI-MS analysis. Spectra were acquired in linear positive ion mode to ensure maximum sensitivity. The lower limit of quantitation was established at 0.5 μg/mL, which is equivalent to 160 fmol peptide. The calibration curve was linear from 0.5 to 7.5 μg/mL, with R(2)>0.98, and permitted quantitation of highly concentrated samples evaluated by dilution integrity testing. All parameters assessed for five validation batches met the FDA guidelines for industry. The method was successfully applied to analysis of clinical samples obtained in a phase I clinical trial following intravenous administration of CIGB-300 at a dose of 1.6 mg/kg body weight. With the exception of Cmax and AUC, pharmacokinetic parameters were similar for ELISA and MALDI-MS methods. Topics: Acetylation; Antineoplastic Agents; Clinical Trials as Topic; Humans; Injections, Intravenous; Limit of Detection; Neoplasms; Peptides, Cyclic; Reference Standards; Reproducibility of Results; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization | 2015 |
Pharmacologic inhibition of the CK2-mediated phosphorylation of B23/NPM in cancer cells selectively modulates genes related to protein synthesis, energetic metabolism, and ribosomal biogenesis.
B23/NPM is a multifunctional nucleolar protein frequently overexpressed, mutated, or rearranged in neoplastic tissues. B23/NPM is involved in diverse biological processes and is mainly regulated by heteroligomer association and posttranslational modification, phosphorylation being a major posttranslational event. While the role of B23/NPM in supporting and/or driving malignant transformation is widely recognized, the particular relevance of its CK2-mediated phosphorylation remains unsolved. Interestingly, the pharmacologic inhibition of such phosphorylation event by CIGB-300, a clinical-grade peptide drug, was previously associated to apoptosis induction in tumor cell lines. In this work, we sought to identify the biological processes modulated by CIGB-300 in a lung cancer cell line using subtractive suppression hybridization and subsequent functional annotation clustering. Our results indicate that CIGB-300 modulates a subset of genes involved in protein synthesis (ES = 8.4, p < 0.001), mitochondrial ATP metabolism (ES = 2.5, p < 0.001), and ribosomal biogenesis (ES = 1.5, p < 0.05). The impairment of these cellular processes by CIGB-300 was corroborated at the molecular and cellular levels by Western blot (P-S6/P-4EBP1, translation), confocal microscopy (JC-1, mitochondrial potential), qPCR (45SrRNA/p21, ribosome biogenesis), and electron microscopy (nucleolar structure, ribosome biogenesis). Altogether, our findings provide new insights on the potential relevance of the CK2-mediated phosphorylation of B23/NPM in cancer cells, revealing at the same time the potentialities of its pharmacological manipulation for cancer therapy. Finally, this work also suggests several candidate gene biomarkers to be evaluated during the clinical development of the anti-CK2 peptide CIGB-300. Topics: Apoptosis; Casein Kinase II; Cell Line, Tumor; Cell Proliferation; Energy Metabolism; Humans; Neoplasms; Nuclear Proteins; Nucleophosmin; Peptides, Cyclic; Phosphorylation; Ribosomes | 2015 |