cx-4945 has been researched along with Neoplasms* in 11 studies
1 review(s) available for cx-4945 and Neoplasms
Article | Year |
---|---|
Exploring the roles of the Cdc2-like kinases in cancers.
The Cdc2-like kinases (CLKs 1-4) are involved in regulating the alternative splicing of a variety of genes. Their activity contributes to important cellular processes such as proliferation, differentiation, apoptosis, migration, and cell cycle regulation. Abnormal expression of CLKs can lead to cancers; therefore, pharmacological inhibition of CLKs may be a useful therapeutic strategy. This review summarises what is known about the roles of each of the CLKs in cancerous cells, as well as the effects of relevant small molecule CLK inhibitors. Topics: Alternative Splicing; Humans; Neoplasms; Phosphorylation; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases | 2022 |
10 other study(ies) available for cx-4945 and Neoplasms
Article | Year |
---|---|
Emerging JWA-targeted Pt(IV) prodrugs conjugated with CX-4945 to overcome chemo-immune-resistance.
Two Pt(IV) prodrugs, Cx-platin-Cl and Cx-DN604-Cl, derived from the conjugation of cisplatin or DN604 with a CK2 inhibitor CX-4945, were constructed to suppress DNA damage repair-related elements. During in vitro biological studies, the Pt(IV) prodrugs had excellent cytotoxicity superior to cisplatin and DN604 to reverse drug resistance. Further mechanistic investigations revealed that the powerful anticancer activity of Cx-platin-Cl and Cx-DN604-Cl arisen from its suppression of JWA-XRCC1-mediated single-strand breaks repair. The emerging Pt(IV) prodrugs inhibited the growth of the xenografted tumors of C57BL6 and nude mice apart from JWA Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; DNA Breaks; Drug Resistance, Neoplasm; Heat-Shock Proteins; Humans; Immune Tolerance; Membrane Transport Proteins; Mice, Inbred C57BL; Mice, Nude; Naphthyridines; Neoplasms; Organoplatinum Compounds; Phenazines; Prodrugs; X-ray Repair Cross Complementing Protein 1 | 2020 |
Protein Kinase CK2: An Emerging Regulator of Immunity.
Although it has historically been studied in the context of cancer, recent literature has highlighted the importance of the highly conserved serine/threonine kinase casein kinase II (CK2) in inflammatory disorders. Most strikingly, CK2 is a major regulator of the Th17-Treg axis relevant to many T cell-driven autoimmune disorders including multiple sclerosis (MS). Topics: Animals; Autoimmune Diseases; Casein Kinase II; Clinical Trials as Topic; Emodin; Humans; Immunity; Immunomodulation; Inflammation; Mice; Molecular Targeted Therapy; Multiple Sclerosis; Naphthyridines; Neoplasms; Phenazines; Signal Transduction; T-Lymphocytes, Regulatory; Th17 Cells | 2018 |
A CK2-targeted Pt(IV) prodrug to disrupt DNA damage response.
A Pt(IV) prodrug, Cx-platin, containing CX-4945 (a CK2 inhibitor) as an axial ligand was designed and prepared by targeting CK2 to disrupt DNA damage response. In vitro study indicated that Cx-platin had superior cytotoxicity to cisplatin against a number of cancer cell lines with distinct CK2-expressed levels, caused CK2-overexpressed cancer cells death via suppressing CK2-mediated DNA damage repair and reversed cisplatin resistance. Mechanistic investigation suggested that the potent antitumor activity of Cx-platin resulted from its major suppression of CK2-phosphorylated MDC1 to combine FHA domain of aprataxin to DNA double strand breaks (DSBs) caused by improved cellular uptakes of Pt and ATM deactivation. Further in vivo tests exhibited that Cx-platin displayed high tumor inhibition rates, increased weight gain, and hardly toxicity effects in contrast to cisplatin. Topics: Adaptor Proteins, Signal Transducing; Animals; Antineoplastic Agents; Ataxia Telangiectasia Mutated Proteins; Casein Kinase II; Cell Cycle Proteins; Cisplatin; DNA Damage; DNA Repair; DNA-Binding Proteins; Dose-Response Relationship, Drug; Drug Combinations; Drug Design; Female; HCT116 Cells; Hep G2 Cells; Humans; Inhibitory Concentration 50; Male; MCF-7 Cells; Mice, Inbred BALB C; Mice, Nude; Molecular Targeted Therapy; Naphthyridines; Neoplasms; Nuclear Proteins; Organoplatinum Compounds; Phenazines; Phosphorylation; Prodrugs; Protein Interaction Domains and Motifs; Protein Kinase Inhibitors; Rats, Sprague-Dawley; Signal Transduction; Time Factors; Trans-Activators; Xenograft Model Antitumor Assays | 2017 |
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 |
CK2 inhibitor CX-4945 suppresses DNA repair response triggered by DNA-targeted anticancer drugs and augments efficacy: mechanistic rationale for drug combination therapy.
Drug combination therapies are commonly used for the treatment of cancers to increase therapeutic efficacy, reduce toxicity, and decrease the incidence of drug resistance. Although drug combination therapies were originally devised primarily by empirical methods, the increased understanding of drug mechanisms and the pathways they modulate provides a unique opportunity to design combinations that are based on mechanistic rationale. We have identified protein kinase CK2 as a promising therapeutic target for combination therapy, because CK2 regulates not just one but many oncogenic pathways and processes that play important roles in drug resistance, including DNA repair, epidermal growth factor receptor signaling, PI3K/AKT/mTOR signaling, Hsp90 machinery activity, hypoxia, and interleukin-6 expression. In this article, we show that CX-4945, a clinical stage selective small molecule inhibitor of CK2, blocks the DNA repair response induced by gemcitabine and cisplatin and synergizes with these agents in models of ovarian cancer. Mechanistic studies show that the enhanced activity is a result of inactivation of XRCC1 and MDC1, two mediator/adaptor proteins that are essential for DNA repair and that require phosphorylation by CK2 for their function. These data position CK2 as a valid pharmacologic target for intelligent drug combinations and support the evaluation of CX-4945 in combination with gemcitabine and platinum-based chemotherapeutics in the clinical setting. Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Casein Kinase II; Cell Line, Tumor; Checkpoint Kinase 2; DNA Repair; Drug Synergism; Female; Humans; Mice; Naphthyridines; Neoplasms; Ovarian Neoplasms; Phenazines; Phosphorylation; Protein Serine-Threonine Kinases; Random Allocation; Signal Transduction; Xenograft Model Antitumor Assays | 2012 |
Combined inhibition of EGFR and CK2 augments the attenuation of PI3K-Akt-mTOR signaling and the killing of cancer cells.
Ser/Thr protein kinase CK2 regulates multiple processes that play important roles in the sensitivity of cancer to epidermal growth factor receptor targeting therapeutics, including PI3K-Akt-mTOR signaling, Hsp90 activity, and inhibition of apoptosis. We hypothesized that top-down inhibition of EGFR, combined with lateral suppression of multiple oncogenic pathways by targeting CK2, would create a pharmacologic synthetic lethal event and result in an improved cancer therapy compared to EGFR inhibition alone. This hypothesis was tested by combining CX-4945, a first-in-class clinical stage inhibitor of CK2, with the EGFR tyrosine kinase inhibitor, erlotinib, in vitro and in vivo in models of non-small cell lung carcinoma, NCI-H2170, and squamous cell carcinoma, A431. Our results demonstrate that combination of CX-4945 with erlotinib results in enhanced attenuation of the PI3K-Akt-mTOR pathway. We also observed an increase in apoptosis, synergistic killing of cancer cells in vitro, as well as improved antitumor efficacy in vivo. Taken together, these data position CK2 as a valid pharmacologic target for drug combinations and support further evaluation of CX-4945 in combination with EGFR targeting agents. Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Casein Kinase II; Cell Line, Tumor; Cell Proliferation; ErbB Receptors; Erlotinib Hydrochloride; Female; Humans; Mice; Naphthyridines; Neoplasms; Phenazines; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Quinazolines; Signal Transduction; TOR Serine-Threonine Kinases | 2012 |
Druggability of the CK2 inhibitor CX-4945 as an anticancer drug and beyond.
Casein kinase 2 (CK2) is involved in multiple cellular processes such as proliferation, apoptosis, and cell cycle. In particular, its over-expression in human cancers is associated with angiogenesis and tumor progression. As a first orally bioavailable small molecule inhibitor of CK2, CX-4945 exerts anti-proliferative activity in human cancer cells by inhibiting the cell cycle and the PI3K/Akt signaling pathway. Additionally, CX-4945 reduces angiogenesis via blockade of hypoxia-inducible factor-1α transcription and suppresses the inflammatory interleukin-6 production in human breast cancer cells. These effects are supported by results from mouse xenograft model investigations. Here, we discuss the druggability of CX-4945 and its potential to be developed as an anti-cancer drug in clinical trials. Topics: Angiogenesis Inhibitors; Animals; Apoptosis; Casein Kinase II; Cell Cycle; Cell Proliferation; Drug Design; Gene Expression Regulation, Neoplastic; Humans; Mice; Naphthyridines; Neoplasms; Neovascularization, Pathologic; Phenazines; Signal Transduction; Xenograft Model Antitumor Assays | 2012 |
Effects of the CK2 inhibitors CX-4945 and CX-5011 on drug-resistant cells.
CK2 is a pleiotropic protein kinase, which regulates many survival pathways and plays a global anti-apoptotic function. It is highly expressed in tumor cells, and is presently considered a promising therapeutic target. Among the many inhibitors available for this kinase, the recently developed CX-4945 and CX-5011 have proved to be very potent, selective and effective in inducing cell death in tumor cells; CX-4945 has recently entered clinical trials. However, no data are available on the efficacy of these compounds to overcome drug resistance, a major reasons of cancer therapy failure. Here we address this point, by studying their effects in several tumor cell lines, each available as variant R resistant to drug-induced apoptosis, and normal-sensitive variant S. We found that the inhibition of endogenous CK2 was very similar in S and R treated cells, with more than 50% CK2 activity reduction at sub-micromolar concentrations of CX-4945 and CX-5011. A consequent apoptotic response was induced both in S and R variants of each pairs. Moreover, the combined treatment of CX-4945 plus vinblastine was able to sensitize to vinblastine R cells that are otherwise almost insensitive to this conventional antitumor drug. Consistently, doxorubicin accumulation in multidrug resistant (MDR) cells was greatly increased by CX-4945.In summary, we demonstrated that all the R variants are sensitive to CX-4945 and CX-5011; since some of the treated R lines express the extrusion pump Pgp, often responsible of the MDR phenotype, we can also conclude that the two inhibitors can successfully overcome the MDR phenomenon. Topics: Apoptosis; Casein Kinase II; Cell Line, Tumor; Cell Survival; Doxorubicin; Drug Resistance, Neoplasm; Drug Synergism; Humans; Naphthyridines; Neoplasms; Phenazines; Protein Kinase Inhibitors; Pyrimidines; Quinolines; Vinblastine | 2012 |
Unprecedented selectivity and structural determinants of a new class of protein kinase CK2 inhibitors in clinical trials for the treatment of cancer.
5-(3-Chlorophenylamino)benzo[c][2,6]naphthyridine-8-carboxylic acid (CX-4945), the first clinical stage inhibitor of protein kinase CK2 for the treatment of cancer, is representative of a new class of CK2 inhibitors with K(i) values in the low nanomolar range and unprecedented selectivity versus other kinases. Here we present the crystal structure of the complexes of CX-4945 and two analogues (CX-5011 and CX-5279) with the catalytic subunit of human CK2. Consistent with their ATP-competitive mode of inhibition, all three compounds bind in the active site of CK2 (type I inhibitors). The tricyclic scaffold of the inhibitors superposes on the adenine of ATP, establishing multiple hydrophobic interactions with the binding cavity. The more extended scaffold, as compared to that of ATP, allows the carboxylic function, shared by all three ligands, to penetrate into the deepest part of the active site where it makes interactions with conserved water W1 and Lys-68, thus accounting for the crucial role of this negatively charged group in conferring high potency to this class of inhibitors. The presence of a pyrimidine in CX-5011 and in CX-5279 instead of a pyridine (as in CX-4945) ring is likely to account for the higher specificity of these compounds whose Gini coefficients, calculated by profiling them against panels of 102 and/or 235 kinases, are significantly higher than that of CX-4945 (0.735 and 0.755, respectively, vs 0.615), marking the highest selectivity ever reported for CK2 inhibitors. Topics: Casein Kinase II; Catalytic Domain; Cell Survival; Crystallography, X-Ray; Humans; Hydrophobic and Hydrophilic Interactions; Models, Molecular; Naphthyridines; Neoplasms; Phenazines; Protein Kinase Inhibitors; Pyrimidines; Quinolines | 2011 |
7-(4H-1,2,4-Triazol-3-yl)benzo[c][2,6]naphthyridines: a novel class of Pim kinase inhibitors with potent cell antiproliferative activity.
A novel class of pan-Pim kinase inhibitors was designed by modifying the CK2 inhibitor CX-4945. Introduction of a triazole or secondary amide functionality on the C-7 position and 2'-halogenoanilines on C-5 resulted in potent inhibitors of the Pim-1 and Pim-2 isoforms, with many analogs active at single digit nanomolar concentrations. The molecules inhibited the phosphorylation at Serine 112 of the apoptosis effector BAD, and had potent antiproliferative effects on the AML cell line MV-4-11 (IC(50) <30 nM). This work delivers an excellent lead-optimization platform for Pim targeting anticancer therapies. Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Humans; Leukemia; Naphthyridines; Neoplasms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-pim-1; Triazoles | 2011 |