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Molecular Pharmacology Jan 2015ON01910.Na [sodium (E)-2-(2-methoxy-5-((2,4,6-trimethoxystyrylsulfonyl)methyl)phenylamino)acetate; Rigosertib, Estybon], a styryl benzylsulfone, is a phase III stage...
ON01910.Na [sodium (E)-2-(2-methoxy-5-((2,4,6-trimethoxystyrylsulfonyl)methyl)phenylamino)acetate; Rigosertib, Estybon], a styryl benzylsulfone, is a phase III stage anticancer agent. This non-ATP competitive kinase inhibitor has multitargeted activity, promoting mitotic arrest and apoptosis. Extensive phase I/II studies with ON01910.Na, conducted in patients with solid tumors and hematologic cancers, demonstrate excellent efficacy. However, issues remain affecting its development. These include incomplete understanding of antitumor mechanisms, low oral bioavailability, and unpredictable pharmacokinetics. We have identified a novel (E)-styrylsulfonyl methylpyridine [(E)-N-(2-methoxy-5-((2,4,6-trimethoxystyrylsulfonyl)methyl)pyridin-3-yl)methanesulfonamide (TL-77)] which has shown improved oral bioavailability compared with ON01910.Na. Here, we present detailed cellular mechanisms of TL-77 in comparison with ON01910.Na. TL-77 displays potent growth inhibitory activity in vitro (GI50 < 1μM against HCT-116 cells), demonstrating 3- to 10-fold greater potency against tumor cell lines when compared with normal cells. Cell-cycle analyses reveal that TL-77 causes significant G2/M arrest in cancer cells, followed by the onset of apoptosis. In cell-free conditions, TL-77 potently inhibits tubulin polymerization. Mitotically arrested cells display multipolar spindles and misalignment of chromosomes, indicating that TL-77 interferes with mitotic spindle assembly in cancer cells. These effects are accompanied by induction of DNA damage, inhibition of Cdc25C phosphorylation [indicative of Plk1 inhibition], and downstream inhibition of cyclin B1. However, kinase assays failed to confirm inhibition of Plk1. Nonsignificant effects on phosphoinositide 3-kinase/Akt signal transduction were observed after TL-77 treatment. Analysis of apoptotic signaling pathways reveals that TL-77 downregulates expression of B-cell lymphoma 2 family proteins (Bid, Bcl-xl, and Mcl-1) and stimulates caspase activation. Taken together, TL-77 represents a promising anticancer agent worthy of further evaluation.
Topics: Antineoplastic Agents; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Glycine; HCT116 Cells; HeLa Cells; Human Umbilical Vein Endothelial Cells; Humans; In Vitro Techniques; MCF-7 Cells; Neoplasms; Signal Transduction; Spindle Apparatus; Styrenes; Sulfonamides; Sulfones; Tubulin
PubMed: 25316768
DOI: 10.1124/mol.114.093245 -
European Journal of Medicinal Chemistry May 2020RAS-RAF pathway presents a valuable target for the cancer treatment due to its important roles in the regulation of tumor proliferation, apoptosis and the obtained...
RAS-RAF pathway presents a valuable target for the cancer treatment due to its important roles in the regulation of tumor proliferation, apoptosis and the obtained resistance. To explore such target a RAS/CRAF interference agent, was therefore conjugated with Pt(IV) prodrugs via ester bond, resulting in total eleven multifunctional Pt(IV) complexes. The complexes could target genomic DNA and disrupt the signaling transduction from RAS protein to CRAF so that block the mitogen-activated protein kinase (MAPK) signaling pathway. Experiments in vitro indicated that all of the Pt(IV) complexes showed potent anti-tumor activity with IC values ranged from 8 nM to 22.55 μM, which were significantly improved as compared with cisplatin (CDDP) whose IC values ranged from 5.45 μM to 9.05 μM. Among them, 26 exerted the best anti-tumor activity in vitro, which not only exhibited excellent cytotoxicity against normal tumor cells, but also against CDDP-resistance cell lines (e.g. A549/CDDP and SKOV-3/CDDP). Importantly, 26 only showed little effect on normal cell lines such as HUEVC and LO2. Besides, the following biological mechanisms studies demonstrated that 26 could efficiently enter. A549 cells, significantly arrest cell cycle at G2/M phase, disrupt the signaling pathway and trigger endogenous caspase apoptosis pathway. Furthermore, results of a xenograft subcutaneous model of A549 tumor showed that 26 could effectively decrease tumor growth rates without causing loss of bodyweight.
Topics: Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Proliferation; Cells, Cultured; Cisplatin; DNA Damage; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Glycine; Humans; Membrane Potential, Mitochondrial; Molecular Structure; Organoplatinum Compounds; Reactive Oxygen Species; Signal Transduction; Structure-Activity Relationship; Sulfones; raf Kinases; ras Proteins
PubMed: 32248002
DOI: 10.1016/j.ejmech.2020.112269 -
Oncology Research Sep 2021Cell cycle deregulation is involved in the pathogenesis of many cancers and is often associated with protein kinase aberrations, including the polo-like kinase 1 (PLK1)....
Cell cycle deregulation is involved in the pathogenesis of many cancers and is often associated with protein kinase aberrations, including the polo-like kinase 1 (PLK1). We used retinoblastoma, an intraocular malignancy that lacks targeted therapy, as a disease model and set out to reveal targetability of PLK1 with a small molecular inhibitor ON-01910.Na. First, transcriptomic analysis on patient retinoblastoma tissues suggested that cell cycle progression was deregulated and confirmed that PLK1 pathway was upregulated. Next, antitumor activity of ON-01910.Na was investigated in both cellular and animal levels. Cytotoxicity induced by ON-01910.Na was tumor specific and dose dependent in retinoblastoma cells, while nontumor cells were minimally affected. In three-dimensional culture, ON-01910.Na demonstrated efficient drug penetrability with multilayer cell death. Posttreatment transcriptomic findings revealed that cell cycle arrest and MAPK cascade activation were induced following PLK1 inhibition and eventually resulted in apoptotic cell death. In Balb/c nude mice, a safe threshold of 0.8 nmol intravitreal dosage of ON-01910.Na was established for intraocular safety, which was demonstrated by structural integrity and functional preservation. Furthermore, intraocular and subcutaneous xenograft were significantly reduced with ON-01910.Na treatments. For the first time, we demonstrated targetability of PLK1 in retinoblastoma by efficiently causing cell cycle arrest and apoptosis. Our study is supportive that local treatment of ON-01910.Na may be a novel, effective modality benefiting patients with PLK1-aberrant tumors.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Gene Expression Profiling; Glycine; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Retinal Neoplasms; Retinoblastoma; Sulfones; Xenograft Model Antitumor Assays; p38 Mitogen-Activated Protein Kinases; Polo-Like Kinase 1
PubMed: 33573708
DOI: 10.3727/096504021X16130322409507 -
Frontiers in Oncology 2023To provide a systematic review of existing meta-analysis on the efficacy, safety and pharmacokinetics of the novel Polo-like kinase-1 (Plk1) inhibitors in various tumor...
OBJECTIVE
To provide a systematic review of existing meta-analysis on the efficacy, safety and pharmacokinetics of the novel Polo-like kinase-1 (Plk1) inhibitors in various tumor treatments, and assess the methodological quality and the strength of evidence of the included meta-analysis.
METHODS
The Medline, PubMed, Embase, etc. were searched and updated on 30 June 2022. 22 eligible clinical trials involving a total of 1256 patients were included for analyses. Randomised controlled trials (RCTs) compared the efficacy or safety, or both of any Plk1 inhibitors with placebo (active or inert) in participants. To be included, studies had to be RCTs, quasi-RCTs, and nonrandomized comparative studies.
RESULTS
A meta-analysis of two trials reported progression-free survival (PFS) of the overall population (effect size (ES), 1.01; 95% confidence intervals (CIs), 0.73-1.30, 0.0%, <0.001) and overall survival (OS) of the overall population (ES, 0.91; 95% CIs, 0.31-1.50, 77.6%, =0.003). 18 adverse events (AEs) reflected that the possibility of occurrence of AEs in the Plk1 inhibitors group was 1.28 times higher than in the control group (odds ratios (ORs), 1.28; 95% CIs,1.02-1.61). The results of meta-analysis showed that the incidence of AEs in the nervous system was the highest (ES, 0.202; 95% CIs, 0.161-0.244), followed by blood system (ES, 0.190; 95% CIs, 0.178-0.201) and digestive system (ES, 0.181; 95% CIs, 0.150-0.213). Rigosertib (ON 01910.Na) was associated with a decreased risk of AEs in digestive system (ES, 0.103; 95% CIs, 0.059-0.147), but BI 2536 and Volasertib (BI 6727) increased risk of AEs in blood system (ES, 0.399; 95% CIs, 0.294-0.504). Five eligible studies reported the pharmacokinetic parameters of the low dosage (100 mg) cohort and the high dosage (200 mg) cohort, and there was no statistical difference in the total plasma clearance, terminal half-life and apparent volume of distribution at steady state.
CONCLUSIONS
Plk1 inhibitors work better in improving OS and they are well tolerated, effective and safe in reducing the severity of illness while improving the quality of life, especially in patients with non-specific tumors, respiratory system tumors, musculoskeletal system tumors, and urinary system tumors. However, they fail to prolong the PFS. From the vertical whole level analysis, compared to other systems in the body, Plk1 inhibitors should be avoided as far as possible for the treatment of tumors related to the blood circulatory system, digestive system and nervous system, which were attributed to the intervention of Plk1 inhibitors associated with an increased risk of AEs in these systems. The toxicity caused by immunotherapy should be carefully considered. Conversely, a horizontal comparison of three different types of Plk1 inhibitors suggested that Rigosertib (ON 01910.Na) might be relatively suitable for the treatment of tumors associated with the digestive system, while Volasertib (BI 6727) might be even less suitable for the treatment of tumors associated with the blood circulation system. Additionally, in the dose selection of Plk1 inhibitors, the low dose of 100 mg should be preferred, and meanwhile, it can also ensure the pharmacokinetic efficacy that is indistinguishable from the high dose of 200 mg.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/, identifier CRD42022343507.
PubMed: 36845678
DOI: 10.3389/fonc.2023.1062885 -
Molecular Cancer Jun 2021While immune checkpoint blockade (ICB) is the current first-line treatment for metastatic melanoma, it is effective for ~ 52% of patients and has dangerous side...
BACKGROUND
While immune checkpoint blockade (ICB) is the current first-line treatment for metastatic melanoma, it is effective for ~ 52% of patients and has dangerous side effects. The objective here was to identify the feasibility and mechanism of RAS/RAF/PI3K pathway inhibition in melanoma to sensitize tumors to ICB therapy.
METHODS
Rigosertib (RGS) is a non-ATP-competitive small molecule RAS mimetic. RGS monotherapy or in combination therapy with ICB were investigated using immunocompetent mouse models of BRAF and BRAF melanoma and analyzed in reference to patient data.
RESULTS
RGS treatment (300 mg/kg) was well tolerated in mice and resulted in ~ 50% inhibition of tumor growth as monotherapy and ~ 70% inhibition in combination with αPD1 + αCTLA4. RGS-induced tumor growth inhibition depends on CD40 upregulation in melanoma cells followed by immunogenic cell death, leading to enriched dendritic cells and activated T cells in the tumor microenvironment. The RGS-initiated tumor suppression was partially reversed by either knockdown of CD40 expression in melanoma cells or depletion of CD8 cytotoxic T cells. Treatment with either dabrafenib and trametinib or with RGS, increased CD40SOX10 melanoma cells in the tumors of melanoma patients and patient-derived xenografts. High CD40 expression level correlates with beneficial T-cell responses and better survival in a TCGA dataset from melanoma patients. Expression of CD40 by melanoma cells is associated with therapeutic response to RAF/MEK inhibition and ICB.
CONCLUSIONS
Our data support the therapeutic use of RGS + αPD1 + αCTLA4 in RAS/RAF/PI3K pathway-activated melanomas and point to the need for clinical trials of RGS + ICB for melanoma patients who do not respond to ICB alone.
TRIAL REGISTRATION
NCT01205815 (Sept 17, 2010).
Topics: Animals; Antineoplastic Agents; CD40 Antigens; Female; Glycine; Humans; Immune Checkpoint Inhibitors; Male; Melanoma; Mice; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Signal Transduction; Sulfones; Xenograft Model Antitumor Assays; raf Kinases; ras Proteins
PubMed: 34092233
DOI: 10.1186/s12943-021-01366-y -
The Journal of Experimental Medicine Jul 2018RAF kinase inhibitors are clinically active in patients with BRAF (V600E) mutant melanoma. However, rarely do tumors regress completely, with the majority of responses...
RAF kinase inhibitors are clinically active in patients with BRAF (V600E) mutant melanoma. However, rarely do tumors regress completely, with the majority of responses being short-lived. This is partially mediated through the loss of negative feedback loops after MAPK inhibition and reactivation of upstream signaling. Here, we demonstrate that the deubiquitinating enzyme USP28 functions through a feedback loop to destabilize RAF family members. Loss of USP28 stabilizes BRAF enhancing downstream MAPK activation and promotes resistance to RAF inhibitor therapy in culture and in vivo models. Importantly, we demonstrate that USP28 is deleted in a proportion of melanoma patients and may act as a biomarker for response to BRAF inhibitor therapy in patients. Furthermore, we identify Rigosertib as a possible therapeutic strategy for USP28-depleted tumors. Our results show that loss of USP28 enhances MAPK activity through the stabilization of RAF family members and is a key factor in BRAF inhibitor resistance.
Topics: Animals; Apoptosis; Cell Line, Tumor; Down-Regulation; Drug Resistance, Neoplasm; F-Box-WD Repeat-Containing Protein 7; Gene Deletion; Glycine; HEK293 Cells; Humans; MAP Kinase Signaling System; Melanoma; Mice; Prognosis; Protein Stability; Proteolysis; Proto-Oncogene Proteins B-raf; Sulfones; Ubiquitin Thiolesterase; Vemurafenib
PubMed: 29880484
DOI: 10.1084/jem.20171960 -
Journal of Medicinal Chemistry Jan 2020Inhibiting/disturbing the RAS/RAF pathway may benefit the treatment of cancer and overcome the resistance. Utilizing such a pathway as the target, nine...
Platinum-Based Modification of Styrylbenzylsulfones as Multifunctional Antitumor Agents: Targeting the RAS/RAF Pathway, Enhancing Antitumor Activity, and Overcoming Multidrug Resistance.
Inhibiting/disturbing the RAS/RAF pathway may benefit the treatment of cancer and overcome the resistance. Utilizing such a pathway as the target, nine styrylbenzylsulfone derivatives generated from the platinum-based modification of the side chain of Rigosertib were designed. Among them, compound showed the most potent antitumor activity in vitro with IC values at the nanomolar level against the tested tumor cell lines and 1000-fold higher than cisplatin against the multidrug resistant cells (A549/CDDP, A549/DOX, and SKOV-3/CDDP cells), while it showed only moderate cytotoxicity against normal cells (HEUVC cells). Compound could clearly disturb signaling transduction between RAS and CRAF by directly bonding to CRAF and inhibit CRAF activation. Besides, the enhanced intracellular platinum level made more potent than cisplatin in DNA damage, reactive oxygen species accumulation, and mitochondrial membrane potential decrease. Moreover, induced apoptosis by the endogenous pathway and efficiently inhibited tumor growth in the A549 xenograft model without side effects.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Coordination Complexes; DNA Damage; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; G2 Phase Cell Cycle Checkpoints; Glycine; Human Umbilical Vein Endothelial Cells; Humans; Mice, Inbred BALB C; Neoplasms; Platinum; Proto-Oncogene Proteins c-raf; Reactive Oxygen Species; Signal Transduction; Sulfones; Xenograft Model Antitumor Assays; ras Proteins
PubMed: 31820986
DOI: 10.1021/acs.jmedchem.9b01223 -
Cells Dec 2020In cancer pharmacology, a drug candidate's therapeutic potential is typically expressed as its ability to suppress cell growth. Different methods in assessing the cell...
In cancer pharmacology, a drug candidate's therapeutic potential is typically expressed as its ability to suppress cell growth. Different methods in assessing the cell phenotype and calculating the drug effect have been established. However, inconsistencies in drug response outcomes have been reported, and it is still unclear whether and to what extent the choice of data post-processing methods is responsible for that. Studies that systematically examine these questions are rare. Here, we compare three established calculation methods on a collection of nine in vitro models of glioblastoma, exposed to a library of 231 clinical drugs. The therapeutic potential of the drugs is determined on the growth curves, using growth inhibition 50% (GI50) and point-of-departure (PoD) as the criteria. An effect is detected on 36% of the drugs when relying on GI50 and on 27% when using PoD. For the area under the curve (AUC), a threshold of 9.5 or 10 could be set to discriminate between the drugs with and without an effect. GI50, PoD, and AUC are highly correlated. The ranking of substances by different criteria varies somewhat, but the group of the top 20 substances according to one criterion typically includes 17-19 top candidates according to another. In addition to generating preclinical values with high clinical potential, we present off-target appreciation of top substance predictions by interrogating the drug response data of non-cancer cells in our calculation technology.
Topics: Antineoplastic Agents; Area Under Curve; Bortezomib; Brain Neoplasms; Cell Line, Tumor; Drug Resistance, Neoplasm; Glycine; Humans; Sulfones
PubMed: 33333810
DOI: 10.3390/cells9122689 -
Scientific Reports Aug 2017In recent years genome-wide RNAi screens have revealed hundreds of cellular factors required for influenza virus infections in human cells. The long-term goal is to...
In recent years genome-wide RNAi screens have revealed hundreds of cellular factors required for influenza virus infections in human cells. The long-term goal is to establish some of them as drug targets for the development of the next generation of antivirals against influenza. We found that several members of the polo-like kinases (PLK), a family of serine/threonine kinases with well-known roles in cell cycle regulation, were identified as hits in four different RNAi screens and we therefore studied their potential as drug target for influenza. We show that knockdown of PLK1, PLK3, and PLK4, as well as inhibition of PLK kinase activity by four different compounds, leads to reduced influenza virus replication, and we map the requirement of PLK activity to early stages of the viral replication cycle. We also tested the impact of the PLK inhibitor BI2536 on influenza virus replication in a human lung tissue culture model and observed strong inhibition of virus replication with no measurable toxicity. This study establishes the PLKs as potential drug targets for influenza and contributes to a more detailed understanding of the intricate interactions between influenza viruses and their host cells.
Topics: A549 Cells; Animals; Antimitotic Agents; Cell Cycle Proteins; Dogs; Glycine; HEK293 Cells; Humans; Influenza A virus; Influenza, Human; Madin Darby Canine Kidney Cells; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Pteridines; RNA Interference; Sulfones; Tumor Suppressor Proteins; Virus Replication; Polo-Like Kinase 1
PubMed: 28819179
DOI: 10.1038/s41598-017-08942-7 -
Cell Apr 2016Oncogenic activation of RAS genes via point mutations occurs in 20%-30% of human cancers. The development of effective RAS inhibitors has been challenging, necessitating...
Oncogenic activation of RAS genes via point mutations occurs in 20%-30% of human cancers. The development of effective RAS inhibitors has been challenging, necessitating new approaches to inhibit this oncogenic protein. Functional studies have shown that the switch region of RAS interacts with a large number of effector proteins containing a common RAS-binding domain (RBD). Because RBD-mediated interactions are essential for RAS signaling, blocking RBD association with small molecules constitutes an attractive therapeutic approach. Here, we present evidence that rigosertib, a styryl-benzyl sulfone, acts as a RAS-mimetic and interacts with the RBDs of RAF kinases, resulting in their inability to bind to RAS, disruption of RAF activation, and inhibition of the RAS-RAF-MEK pathway. We also find that ribosertib binds to the RBDs of Ral-GDS and PI3Ks. These results suggest that targeting of RBDs across multiple signaling pathways by rigosertib may represent an effective strategy for inactivation of RAS signaling.
Topics: Amino Acid Sequence; Animals; Cell Cycle Proteins; Cell Transformation, Neoplastic; Crystallography, X-Ray; Dimerization; Glycine; Humans; MAP Kinase Signaling System; Mice; Mice, Nude; Models, Molecular; Molecular Sequence Data; Nuclear Magnetic Resonance, Biomolecular; Pancreatic Neoplasms; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; RNA-Binding Proteins; Sequence Alignment; Signal Transduction; Sulfones; ras Proteins; Polo-Like Kinase 1
PubMed: 27104980
DOI: 10.1016/j.cell.2016.03.045