Structural Basis of Splicing Modulation by Antitumor Macrolide Compounds.

SF3B is a multi-protein complex essential for branch site (BS) recognition and selection during pre-mRNA splicing. Several splicing modulators with antitumor activity bind SF3B and thereby modulate splicing. Here we report the crystal structure of a human SF3B core in complex with pladienolide B (PB), a macrocyclic splicing modulator and potent inhibitor of tumor cell proliferation. PB stalls SF3B in an open conformation by acting like a wedge within a hinge, modulating SF3B's transition to the closed conformation needed to form the BS adenosine-binding pocket and stably accommodate the BS/U2 duplex. This work explains the structural basis for the splicing modulation activity of PB and related compounds, and reveals key interactions between SF3B and a common pharmacophore, providing a framework for future structure-based drug design.

Discovery of a potent and selective JAK1-targeting PROTAC degrader with anti-tumor activities.

Aberrant activation of the JAK-STAT pathway is evident in various human diseases including cancers. Proteolysis targeting chimeras (PROTACs) provide an attractive strategy for developing novel JAK-targeting drugs. Herein, a series of CRBN-directed JAK-targeting PROTACs were designed and synthesized utilizing a JAK1/JAK2 dual inhibitor-momelotinib as the warhead. The most promising compound 10c exhibited both good enzymatic potency and cellular antiproliferative effects. Western blot analysis revealed that compound 10c effectively and selectively degraded JAK1 in a proteasome-dependent manner (DC50 = 214 nM). Moreover, PROTAC 10c significantly suppressed JAK1 and its key downstream signaling. Together, compound 10c may serve as a novel lead compound for antitumor drug discovery.

Discovery of Novel Antitumor Small-Molecule Agent with Dual Action of CDK2/p-RB and MDM2/p53.

Cell cycle-dependent kinase 2 (CDK2) is located downstream of CDK4/6 in the cell cycle and regulates cell entry into S-phase by binding to Cyclin E and hyper-phosphorylating Rb. Proto-oncogene murine double minute 2 (MDM2) is a key negative regulator of p53, which is highly expressed in tumors and plays an important role in tumorigenesis and progression. In this study, we identified a dual inhibitor of CDK2 and MDM2, III-13, which had good selectivity for inhibiting CDK2 activity and significantly reduced MDM2 expression. In vitro results showed that III-13 inhibited proliferation of a wide range of tumor cells, regardless of whether Cyclin E1 (CCNE1) was overexpressed or not. The results of in vivo experiments showed that III-13 significantly inhibited proliferation of tumor cells and did not affect body weight of mice. The results of the druggability evaluation showed that III-13 was characterized by low bioavailability and poor membrane permeability when orally administered, suggesting the necessity of further structural modifications. Therefore, this study provided a lead compound for antitumor drugs, especially those against CCNE1-amplified tumor proliferation.

The Copper Reduction Potential Determines the Reductive Cytotoxicity: Relevance to the Design of Metal-Organic Antitumor Drugs.

Copper-organic compounds have gained momentum as potent antitumor drug candidates largely due to their ability to generate an oxidative burst upon the transition of Cu2+ to Cu1+ triggered by the exogenous-reducing agents. We have reported the differential potencies of a series of Cu(II)-organic complexes that produce reactive oxygen species (ROS) and cell death after incubation with N-acetylcysteine (NAC). To get insight into the structural prerequisites for optimization of the organic ligands, we herein investigated the electrochemical properties and the cytotoxicity of Cu(II) complexes with pyridylmethylenethiohydantoins, pyridylbenzothiazole, pyridylbenzimidazole, thiosemicarbazones and porphyrins. We demonstrate that the ability of the complexes to kill cells in combination with NAC is determined by the potential of the Cu+2 → Cu+1 redox transition rather than by the spatial structure of the organic ligand. For cell sensitization to the copper-organic complex, the electrochemical potential of the metal reduction should be lower than the oxidation potential of the reducing agent. Generally, the structural optimization of copper-organic complexes for combinations with the reducing agents should include uncharged organic ligands that carry hard electronegative inorganic moieties.

Synthesis and In Vitro Antitumor Activity Evaluation of Gefitinib-1,2,3-Triazole Derivatives.

In this study, 14 structurally novel gefitinib-1,2,3-triazole derivatives were synthesized using a click chemistry approach and characterized by 1H NMR, 13C NMR and high-resolution mass spectrometry (HRMS). Preliminary cell counting kit-8 results showed that most of the compounds exhibit excellent antitumor activity against epidermal growth factor receptor wild-type lung cancer cells NCI-H1299, A549 and NCI-H1437. Among them, 4b and 4c showed the most prominent inhibitory effects. The half maximal inhibitory concentration (IC50) values of 4b were 4.42 ± 0.24 µM (NCI-H1299), 3.94 ± 0.01 µM (A549) and 1.56 ± 0.06 µM (NCI-1437). The IC50 values of 4c were 4.60 ± 0.18 µM (NCI-H1299), 4.00 ± 0.08 µM (A549) and 3.51 ± 0.05 µM (NCI-H1437). Furthermore, our results showed that 4b and 4c could effectively inhibit proliferation, colony formation and cell migration in a concentration-dependent manner, as well as induce apoptosis in H1299 cells. In addition, 4b and 4c exerted its anti-tumor effects by inducing cell apoptosis, upregulating the expression of cleaved-caspase 3 and cleaved-PARP and downregulating the protein levels of Bcl-2. Based on these results, it is suggested that 4b and 4c be developed as potential new drugs for lung cancer treatment.

Advances of antitumor drug discovery in traditional Chinese medicine and natural active products by using multi-active components combination.

The antitumor efficacy of Chinese herbal medicines has been widely recognized. Leading compounds such as sterols, glycosides, flavonoids, alkaloids, terpenoids, phenylpropanoids, and polyketides constitute their complex active components. The antitumor monomers derived from Chinese medicine possess an attractive anticancer activity. However, their use was limited by low bioavailability, significant toxicity, and side effects, hindering their clinical applications. Recently, new chemical entities have been designed and synthesized by combining natural drugs with other small drug molecules or active moieties to improve the antitumor activity and selectivity, and reduce side effects. Such a novel conjugated drug that can interact with several vital biological targets in cells may have a more significant or synergistic anticancer activity than a single-molecule drug. In addition, antitumor conjugates could be obtained by combining pharmacophores containing two or more known drugs or leading compounds. Based on these studies, the new drug research and development could be greatly shortened. This study reviews the research progress of conjugates with antitumor activity based on Chinese herbal medicine. It is expected to serve as a valuable reference to antitumor drug research and clinical application of traditional Chinese medicine.

Wireframe DNA Origami for the Cellular Delivery of Platinum(II)-Based Drugs.

The DNA origami method has revolutionized the field of DNA nanotechnology since its introduction. These nanostructures, with their customizable shape and size, addressability, nontoxicity, and capacity to carry bioactive molecules, are promising vehicles for therapeutic delivery. Different approaches have been developed for manipulating and folding DNA origami, resulting in compact lattice-based and wireframe designs. Platinum-based complexes, such as cisplatin and phenanthriplatin, have gained attention for their potential in cancer and antiviral treatments. Phenanthriplatin, in particular, has shown significant antitumor properties by binding to DNA at a single site and inhibiting transcription. The present work aims to study wireframe DNA origami nanostructures as possible carriers for platinum compounds in cancer therapy, employing both cisplatin and phenanthriplatin as model compounds. This research explores the assembly, platinum loading capacity, stability, and modulation of cytotoxicity in cancer cell lines. The findings indicate that nanomolar quantities of the ball-like origami nanostructure, obtained in the presence of phenanthriplatin and therefore loaded with that specific drug, reduced cell viability in MCF-7 (cisplatin-resistant breast adenocarcinoma cell line) to 33%, while being ineffective on the other tested cancer cell lines. The overall results provide valuable insights into using wireframe DNA origami as a highly stable possible carrier of Pt species for very long time-release purposes.

Solubility and Thermodynamics Data of Cabozantinib Malate in Various Aqueous Solutions of Dimethyl Sulfoxide at Different Temperatures.

Cabozantinib malate (CBZM), a new anticancer medication, has been studied for its solubility and thermodynamic properties in a variety of {dimethyl sulfoxide (DMSO) + water (H2O)} mixtures at 298.2-318.2 K and 101.1 kPa. Using the shake flask technique, the solubility of CBZM was assessed and the results were correlated to the van't Hoff, Apelblat, Buchowski-Ksiazczak λh, Yalkowsky-Roseman, Jouyban-Acree, and Jouyban-Acree-van't Hoff models. There was a significant correlation between the experimental CBZM solubility data and all computational models, as evidenced by the error values for all computational models being less than 5.0%. Temperature and DMSO mass percentage improved the CBZM mole fraction solubility in the cosolvent solutions of {DMSO + H2O}. At 318.2 K, pure DMSO had the highest mole fraction solubility of CBZM (4.38 × 10-2), whereas pure H2O had the lowest mole fraction solubility (2.24 × 10-7 at 298.2 K). The positive values of computed thermodynamic parameters indicated that the dissolution of CBZM was endothermic and entropy-driven in all of the {DMSO + H2O} solutions investigated. It was found that the CBZM solvation in {DMSO + H2O} solutions is governed by enthalpy. When compared to CBZM-H2O, CBZM-DMSO showed the highest molecular interactions. The findings of this investigation demonstrated that DMSO has a great deal of potential for CBZM solubilization in H2O.

Procedures for application of the extended dosing after antitumor drug clinical trials. / æŠ—è‚¿ç˜¤è¯ç‰©ä¸´åºŠè¯•éªŒå—è¯•è€ å‡ºç»„åŽå»¶ä¼¸ç»™è¯ç”³è¯·ç¨‹åº.

New drug clinical trials have been considered as a positive way for treating cancer by cancer patients and doctors, and the extended dosing is a special way for patients' withdrawal from antitumor clinical trials to obtain investigational new drugs. However, neither the regulations of expanded dosing nor the detail documents for expanded dosing have been officially published in China. At present, expanded dosing of investigational drugs is still at the exploratory stage in various medical institutions, and a complete management system has not been established to meet patients' urgent needs for drug use. Based on the practical experience of extended dosing in Hunan Cancer Hospital, this paper preliminarily explored the application procedures and ethical review requirements of extended dosing for subjects in antitumor clinical trials. It is necessary to clarify the responsibilities of all patients in the procedure and establish a patient-medical institution-sponsor joint application system. In the process of ethical review, it is recommended that all parties fully consider the risks and benefits of extended dosing for patients, and then the ethics committee makes a comprehensive assessment to decide whether to approve extended dosing.

Heterocyclic ring expansion yields anthraquinone derivatives potent against multidrug resistant tumor cells.

Chemical modifications of anthraquiones are aimed at novel derivatives with improved antitumor properties. Emergence of multidrug resistance (MDR) due to overexpression of transmembrane ATP binding cassette transporters, in particular, MDR1/P-glycoprotein (Pgp), can limit the use of anthraquinone based drugs. Previously we have demonstrated that annelation of modified five-membered heterocyclic rings with the anthraquinone core yielded a series of compounds with optimized antitumor properties. In the present study we synthesized a series of anthraquinone derivatives with six-membered heterocycles. Selected new compounds showed the ability to kill parental and MDR tumor cell lines at low micromolar concentrations. Molecular docking into the human Pgp model revealed a stronger interaction of 2-methylnaphtho[2,3-g]quinoline-3-carboxamide 17 compared to naphtho[2,3-f]indole-3-carboxamide 3. The time course of intracellular accumulation of compound 17 in parental K562 leukemia cells and in Pgp-positive K562/4 subline was similar. In contrast, compound 3 was readily effluxed from K562/4 cells and was significantly less potent for this subline than for K562 cells. Together with reported strategies of drug optimization of the anthracycline core, these results add ring expansion to the list of perspective modifications of heteroarene-fused anthraquinones.

Pharmacodynamic, pharmacokinetic, and phase 1a study of bisthianostat, a novel histone deacetylase inhibitor, for the treatment of relapsed or refractory multiple myeloma.

HDAC inhibitors (HDACis) have been intensively studied for their roles and potential as drug targets in T-cell lymphomas and other hematologic malignancies. Bisthianostat is a novel bisthiazole-based pan-HDACi evolved from natural HDACi largazole. Here, we report the preclinical study of bisthianostat alone and in combination with bortezomib in the treatment of multiple myeloma (MM), as well as preliminary first-in-human findings from an ongoing phase 1a study. Bisthianostat dose dependently induced acetylation of tubulin and H3 and increased PARP cleavage and apoptosis in RPMI-8226 cells. In RPMI-8226 and MM.1S cell xenograft mouse models, oral administration of bisthianostat (50, 75, 100 mg·kg-1·d-1, bid) for 18 days dose dependently inhibited tumor growth. Furthermore, bisthianostat in combination with bortezomib displayed synergistic antitumor effect against RPMI-8226 and MM.1S cell in vitro and in vivo. Preclinical pharmacokinetic study showed bisthianostat was quickly absorbed with moderate oral bioavailability (F% = 16.9%-35.5%). Bisthianostat tended to distribute in blood with Vss value of 0.31 L/kg. This distribution parameter might be beneficial to treat hematologic neoplasms such as MM with few side effects. In an ongoing phase 1a study, bisthianostat treatment was well tolerated and no grade 3/4 nonhematological adverse events (AEs) had occurred together with good pharmacokinetics profiles in eight patients with relapsed or refractory MM (R/R MM). The overall single-agent efficacy was modest, stable disease (SD) was identified in four (50%) patients at the end of first dosing cycle (day 28). These preliminary in-patient results suggest that bisthianostat is a promising HDACi drug with a comparable safety window in R/R MM, supporting for its further phase 1b clinical trial in combination with traditional MM therapies.

Cucurbitacin B regulates lung cancer cell proliferation and apoptosis via inhibiting the IL-6/STAT3 pathway through the lncRNA XIST/miR-let-7c axis.

CONTEXT: Lung cancer, the most common type of cancer, has a high mortality rate. Cucurbitacin B (CuB), a natural compound extracted from Cucurbitaceae plants, has antitumor effects. OBJECTIVE: We investigated the role of CuB on lung cancer and its potential mechanisms. MATERIALS AND METHODS: A549 cells were treated with 0.1, 0.3, 0.6, and 0.9 µM CuB for 12, 24, and 48 h or untreated. Gene and protein levels were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Enzyme-linked immunosorbent assay (ELISA) detected inflammatory factors levels (TNF-α and IL-10). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry, and colony formation assays measured cell viability, apoptosis, and proliferation. The interaction between miR-let-7c and long non-coding RNA X inactive-specific transcript (XIST) or interleukin-6 (IL-6) was verified by dual-luciferase reporter assays. RESULTS: CuB treatment inhibited the proliferation of lung cancer cells and promoted cell apoptosis, and increased the expression of Bax and cleaved caspase3, decreased cyclin B1 and Bcl-2 expression. CuB suppressed XIST and IL-6 expression, and enhanced miR-let-7c expression. XIST silencing enhanced the inhibitory effect of CuB on cell proliferation and the promotion effect on apoptosis via upregulating miR-let-7c. Moreover, XIST targeted miR-let-7c to activate the IL-6/STAT axis. MiR-let-7c overexpression enhanced the regulatory effect of CuB on proliferation and apoptosis via suppressing the IL-6/STAT3 pathway. DISCUSSION AND CONCLUSION: CuB regulated cell proliferation and apoptosis by inhibiting the XIST/miR-let-7c/IL-6/STAT3 axis in lung cancer. These findings indicate CuB may have the possibility of clinical application in lung cancer treatment.

Visualization of the cancer cell cycle by tissue-clearing technology using the Fucci reporter system.

Tissue-clearing technology is an emerging imaging technique currently utilized not only in neuroscience research but also in cancer research. In our previous reports, tissue-clearing methods were used for the detection of metastatic tumors. Here, we showed that the cell cycles of primary and metastatic tumors were visualized by tissue-clearing methods using a reporter system. First, we established cancer cell lines stably expressing fluorescent ubiquitination-based cell cycle indicator (Fucci) reporter with widely used cancer cell lines A549 and 4T1. Fluorescence patterns of the Fucci reporter were investigated in various tumor inoculation models in mice. Interestingly, fluorescence patterns of the Fucci reporter of tumor colonies were different between various organs, and even among colonies in the same organs. The effects of antitumor drugs were also evaluated using these Fucci reporter cells. Of the three antitumor drugs studied, 5-fluorouracil treatment on 4T1-Fucci cells resulted in characteristic fluorescent patterns by the induction of G2 /M arrest both in vitro and in vivo. Thus, the combination of a tissue-clearing method with the Fucci reporter is useful for analyzing the mechanisms of cancer metastasis and drug resistance.

Functionalized azobenzene platinum(II) complexes as putative anticancer compounds.

The synthesis and characterization of four platinum(II) complexes using azobenzenes conveniently functionalized as ligands has been carried out. The characteristic photochemical behavior of the complexes due to the presence of azobenzene-type ligands and the role of the ligands in the activation of the complexes has been studied. Their promising cytotoxicity observed in HeLa cells prompted us to study the mechanism of action of these complexes as cytostatic agents. The interaction of the compounds with DNA, studied by circular dichroism, revealed a differential activity of the Pt(II) complexes upon irradiation. The intercalation abilities of the complexes as well as their reactivity with common proteins present in the blood stream allows to confirm some of the compounds obtained as good anticancer candidates.

Design, synthesis and biological evaluation of novel molecules as potent PARP-1 inhibitors.

Two series of novel compounds with inhibition activity against PARP-1 were designed and synthesized. All target compounds were evaluated for their PARP-1 inhibition activity, and compounds with high PARP-1 inhibition activity were selected to assess for cellular assays in vitro. Among them, compound II-4 displayed impressive results in both PARP-1 enzyme inhibition with IC50 value of 0.51 nM and anti-proliferation activity against HCT116 and HCC1937 cell lines with IC50 values of 6.62 nM and 12.65 nM, respectively. Also, II-4 exhibited good metabolic stability in vitro with t1/2 of 173.25 min and CLint of 0.04 mL/min/mg. Prediction of molecular properties and protein docking were applied to structure design. Our study provides potential lead compounds and design directions for the development of PARP-1 inhibitors.

In vivo-in vitro correlation of antitumor activity of heat shock protein 90 (HSP90) inhibitors with a pharmacokinetics/pharmacodynamics analysis using NCI-N87 xenograft mice.

The in vitro antitumor activity (e.g. IC50) of anticancer drugs is important for selecting candidate compounds for in vivo drug efficacy study in the early stage of drug discovery. In this study, we investigated the relationship between in vitro IC50 and in vivo EC50 using six heat shock protein 90 (HSP90) inhibitors.IC50 of each compound was calculated from in vitro cell proliferation assays using the NCI-N87 cancer cell line. Each compound was administered to NCI-N87 xenograft mice, and EC50 and the maximum tumour-killing rate constant were calculated from pharmacokinetics/pharmacodynamics analyses using plasma concentrations and tumour volumes.IC50 obtained in vitro was poorly correlated with EC50 obtained in vivo, while a good correlation (r = 0.856) was observed between them when corrected with the unbound fraction ratio.The results of this study using of HSP90 inhibitors as model compounds suggest importance of the consideration of an unbound fraction to evaluate the relationship between IC50 and EC50. These results will contribute to improvement in the prediction accuracy of in vivo drug efficacy from in vitro activity and the efficiency of drug discovery research.

Improvement of conventional anti-cancer drugs as new tools against multidrug resistant tumors.

Multidrug resistance (MDR) is the dominant cause of the failure of cancer chemotherapy. The design of antitumor drugs that are able to evade MDR is rapidly evolving, showing that this area of biomedical research attracts great interest in the scientific community. The current review explores promising recent approaches that have been developed with the aim of circumventing or overcoming MDR. Encouraging results have been obtained in the investigation of the MDR-modulating properties of various classes of natural compounds and their analogues. Inhibition of P-gp or downregulation of its expression have proven to be the main mechanisms by which MDR can be surmounted. The use of hybrid molecules that are able to simultaneously interact with two or more cancer cell targets is currently being explored as a means to circumvent drug resistance. This strategy is based on the design of hybrid compounds that are obtained either by merging the structural features of separate drugs, or by conjugating two drugs or pharmacophores via cleavable/non-cleavable linkers. The approach is highly promising due to the pharmacokinetic and pharmacodynamic advantages that can be achieved over the independent administration of the two individual components. However, it should be stressed that the task of obtaining successful multivalent drugs is a very challenging one. The conjugation of anticancer agents with nitric oxide (NO) donors has recently been developed, creating a particular class of hybrid that can combat tumor drug resistance. Appropriate NO donors have been shown to reverse drug resistance via nitration of ABC transporters and by interfering with a number of metabolic enzymes and signaling pathways. In fact, hybrid compounds that are produced by covalently attaching NO-donors and antitumor drugs have been shown to elicit a synergistic cytotoxic effect in a variety of drug resistant cancer cell lines. Another strategy to circumvent MDR is based on nanocarrier-mediated transport and the controlled release of chemotherapeutic drugs and P-gp inhibitors. Their pharmacokinetics are governed by the nanoparticle or polymer carrier and make use of the enhanced permeation and retention (EPR) effect, which can increase selective delivery to cancer cells. These systems are usually internalized by cancer cells via endocytosis and accumulate in endosomes and lysosomes, thus preventing rapid efflux. Other modalities to combat MDR are described in this review, including the pharmaco-modulation of acridine, which is a well-known scaffold in the development of bioactive compounds, the use of natural compounds as means to reverse MDR, and the conjugation of anticancer drugs with carriers that target specific tumor-cell components. Finally, the outstanding potential of in silico structure-based methods as a means to evaluate the ability of antitumor drugs to interact with drug transporters is also highlighted in this review. Structure-based design methods, which utilize 3D structural data of proteins and their complexes with ligands, are the most effective of the in silico methods available, as they provide a prediction regarding the interaction between transport proteins and their substrates and inhibitors. The recently resolved X-ray structure of human P-gp can help predict the interaction sites of designed compounds, providing insight into their binding mode and directing possible rational modifications to prevent them from becoming P-gp drug substrates. In summary, although major efforts were invested in the search for new tools to combat drug resistant tumors, they all require further implementation and methodological development. Further investigation and progress in the abovementioned strategies will provide significant advances in the rational combat against cancer MDR.

Synthesis and Characterization of New Biodegradable Injectable Thermosensitive Smart Hydrogels for 5-Fluorouracil Delivery.

In this paper, injectable, thermosensitive smart hydrogel local drug delivery systems (LDDSs) releasing the model antitumour drug 5-fluorouracil (5-FU) were developed. The systems were based on biodegradable triblock copolymers synthesized via ring opening polymerization (ROP) of ε-caprolactone (CL) in the presence of poly(ethylene glycol) (PEG) and zirconium(IV) acetylacetonate (Zr(acac)4), as co-initiator and catalyst, respectively. The structure, molecular weight (Mn) and molecular weight distribution (D) of the synthesized materials was studied in detail using nuclear magnetic resonance (NMR) and gel permeation chromatography (GPC) techniques; the optimal synthesis conditions were determined. The structure corresponded well to the theoretical assumptions. The produced hydrogels demonstrated a sharp sol-gel transition at temperature close to physiological value, forming a stable gel with good mechanical properties at 37 °C. The kinetics and mechanism of in vitro 5-FU release were characterized by zero order, first order, Higuchi and Korsmeyer-Peppas mathematical models. The obtained results indicate good release control; the kinetics were generally defined as first order according to the predominant diffusion mechanism; and the total drug release time was approximately 12 h. The copolymers were considered to be biodegradable and non-toxic; the resulting hydrogels appear to be promising as short-term LDDSs, potentially useful in antitumor therapy.

Discovery of novel dual c-Met/HDAC inhibitors as a promising strategy for cancer therapy.

Owing to the low efficacy and acquired resistance in clinical trials of c-Met inhibitors, based on the synergistic effects between c-Met and HDAC, novel c-Met and HDAC dual inhibitors were designed and synthesized. We introduced 2-pyrrolidinone to form the 5-atoms linker for c-Met inhibitor and hydroxamic acid as a zinc binding motif for HDAC inhibitor. The highly active dual inhibitor 15f showed excellent and balanced activity against both c-Met (IC50 = 12.50 nM) and HDAC1 (IC50 = 26.97 nM). In those tested tumor cell lines, 15f exhibits efficient antiproliferative activity with greater potency than Vorinostat (SAHA) and Cabozantinib (XL184). However, by comparing with an equimolar mixture of SAHA and Foretinib, we did not observe the compounds showed clearly synergistic antiproliferative effect. Nevertheless, compound 15f was found to induce apoptosis and cause cell cycle arrest in G2/M phase. This proof-of-concept study provides an efficient strategy for discovery of multitarget antitumor drugs.

Deeping in the Role of the MAP-Kinases Interacting Kinases (MNKs) in Cancer.

The mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) are involved in oncogenic transformation and can promote metastasis and tumor progression. In human cells, there are four MNKs isoforms (MNK1a/b and MNK2a/b), derived from two genes by alternative splicing. These kinases play an important role controlling the expression of specific proteins involved in cell cycle, cell survival and cell motility via eukaryotic initiation factor 4E (eIF4E) regulation, but also through other substrates such as heterogeneous nuclear ribonucleoprotein A1, polypyrimidine tract-binding protein-associated splicing factor and Sprouty 2. In this review, we provide an overview of the role of MNK in human cancers, describing the studies conducted to date to elucidate the mechanism involved in the action of MNKs, as well as the development of MNK inhibitors in different hematological cancers and solid tumors.