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1.
Nano Lett ; 24(27): 8351-8360, 2024 Jul 10.
Article in English | MEDLINE | ID: mdl-38916238

ABSTRACT

Targeting telomere maintenance has emerged as a promising strategy for hepatocellular carcinoma (HCC) treatment. However, given the duality of the telomere-telomerase axis in telomere maintenance, a comprehensive strategy is urgently needed. Herein, we develop a poly(amino acid) (D-PAAs)-based strategy for spatiotemporal codelivery of telomerase inhibitor, BIBR1523, and AKT inhibitor, isobavachalcone. By leveraging D-PAAs' modifiability, we synthesize polymer-inhibitor conjugates (PB and PI) and a folic acid-decorated tumor-targeting vector (PF). These building blocks undergo micellization to fabricate a codelivery nanomedicine (P-BI@P-FA) by exploiting D-PAAs' noncovalent assembly. P-BI@P-FA improves the pharmacokinetics, tumor selectivity, and bioavailability of small molecule inhibitors and initiates a dual telomere-specific inhibition by combining telomerase deactivation with telomere disruption. Furthermore, a hybrid tumor-targeting magnetic nanosystem is designed using D-PAAs and manganese dioxide to showcase magnetic resonance imaging capacities. Our D-PAAs-based strategy addresses the pressing need for telomere-specific HCC treatment while allowing for diagnostic application, presenting a promising avenue for nanomedicine design.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Magnetic Resonance Imaging , Nanomedicine , Telomerase , Telomere , Carcinoma, Hepatocellular/diagnostic imaging , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Telomerase/antagonists & inhibitors , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/drug therapy , Humans , Nanomedicine/methods , Telomere/metabolism , Magnetic Resonance Imaging/methods , Animals , Mice , Cell Line, Tumor , Amino Acids/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use
2.
Curr Med Res Opin ; 37(8): 1275-1281, 2021 08.
Article in English | MEDLINE | ID: mdl-33830834

ABSTRACT

OBJECTIVE: This study aimed to determine rates of hospitalization and in-hospital mortality in the first year following amyloidosis diagnosis with cardiac involvement using observational databases. METHODS: Three administrative claims databases, IBM MarketScan® Commercial Claims and Encounters (CCAE), IBM MarketScan® Multi-State Medicare Database (MDCR), and Optum's de-identified Clinformatics® Data Mart Database (Optum) were analyzed. Adults ≥18 years old, with a diagnosis of amyloidosis and evidence of cardiac involvement (i.e. heart failure, heart block, or cardiomyopathy) but no hepatic/renal failure prior to amyloidosis diagnosis were included for analysis. The primary analyses identified patients between 01-01-2010 and 31-12-2017 period. We calculated the rates of hospitalization and in-hospital mortality within 1 year after the initial diagnosis of amyloidosis. A sensitivity analysis was conducted for patients identified in Optum database during 2004-2011 period, which provided additional mortality information. RESULTS: A total of 419, 654, and 922 patients from CCAE, MDCR, and Optum were identified during 2010-2017 period, with mean age of 55.6, 77.8, and 74.2 years, respectively. Within 1 year following initial amyloidosis diagnosis, incidence rates (95% confidence interval [CI]) of hospitalization were 78.4 (66.3, 90.4), 78.6 (69.2, 87.9), and 61.2 (54.4, 68.0) per 100 person-years, rates of in-hospital mortality were 16.5 (11.8, 21.3), 8.4 (5.7, 11.0), and 17.7 (14.5, 21.0) per 100 person-years, in CCAE, MDCR, and Optum, respectively. The mortality rate from the sensitivity analysis among patients identified in Optum 2004-2011 period was higher compared with Optum 2010-2017 period. CONCLUSIONS: The results from this study indicate that amyloidosis with cardiac involvement is a condition with high rates of hospitalization and mortality in the first year after initial diagnosis. Future studies are needed to further evaluate the outcomes within the subtypes of amyloidosis and understand the risk factors associated with poor prognoses.


Subject(s)
Amyloidosis , Medicare , Aged , Amyloidosis/diagnosis , Amyloidosis/epidemiology , Databases, Factual , Hospitalization , Humans , Incidence , Infant, Newborn , Middle Aged , Retrospective Studies , United States/epidemiology
3.
Sci Total Environ ; 728: 138853, 2020 Aug 01.
Article in English | MEDLINE | ID: mdl-32353802

ABSTRACT

The high moisture content of wet sewage sludge generated from wastewater treatment process not only brings high cost of sewage disposal, but also limits its utilization as resource. In this study, an efficient strategy of directly utilizing wet sludge to develop advanced carbocatalyst via a hydrothermal coupled pyrolysis process was proposed. The possible application of as-synthesized carbocatalyst was evaluated by activating peroxymonosulfate (PMS) to degrade a model pollutant of sulfamethoxazole (SMX). Experimental results showed that about 100% of SMX and 59% of total organic carbon (TOC) could be removed within 15 min. Moisture content in wet sludge also affected the performances of as-obtained carbocatalysts. Further studies verified that singlet oxygen (1O2) dominated SMX degradation, which was generated in the process of PMS activation by CO groups on the surface of carbocatalyst. In the preliminary ecological test, a lower ecotoxicity of SMX degradation solution compared with the original solution was observed. This study demonstrated the feasibility of directly utilizing wet sludge for advanced carbocatalyst fabrication, which provided another solution for wet sludge treatment and utilization.


Subject(s)
Sulfamethoxazole , Water Pollutants, Chemical , Carbon , Peroxides , Sewage
4.
Proc Natl Acad Sci U S A ; 116(14): 6812-6817, 2019 04 02.
Article in English | MEDLINE | ID: mdl-30894493

ABSTRACT

Aberrant activation of Wnt/ß-catenin signaling occurs frequently in cancer. However, therapeutic targeting of this pathway is complicated by the role of Wnt in stem cell maintenance and tissue homeostasis. Here, we evaluated antibodies blocking 6 of the 10 human Wnt/Frizzled (FZD) receptors as potential therapeutics. Crystal structures revealed a common binding site for these monoclonal antibodies (mAbs) on FZD, blocking the interaction with the Wnt palmitoleic acid moiety. However, these mAbs displayed gastrointestinal toxicity or poor plasma exposure in vivo. Structure-guided engineering was used to refine the binding of each mAb for FZD receptors, resulting in antibody variants with improved in vivo tolerability and developability. Importantly, the lead variant mAb significantly inhibited tumor growth in the HPAF-II pancreatic tumor xenograft model. Taken together, our data demonstrate that anti-FZD cancer therapeutic antibodies with broad specificity can be fine-tuned to navigate in vivo exposure and tolerability while driving therapeutic efficacy.


Subject(s)
Antibody Specificity , Antineoplastic Agents, Immunological , Frizzled Receptors/antagonists & inhibitors , Pancreatic Neoplasms , Protein Engineering , Animals , Antibody Specificity/genetics , Antibody Specificity/immunology , Antineoplastic Agents, Immunological/immunology , Antineoplastic Agents, Immunological/pharmacokinetics , Antineoplastic Agents, Immunological/pharmacology , Cell Line, Tumor , Female , Frizzled Receptors/genetics , Frizzled Receptors/immunology , HEK293 Cells , Humans , Mice , Mice, Nude , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/pathology , Xenograft Model Antitumor Assays
5.
Curr Med Res Opin ; 34(12): 2053-2061, 2018 12.
Article in English | MEDLINE | ID: mdl-29932775

ABSTRACT

OBJECTIVE: Atrial fibrillation, peripheral and coronary artery disease, and venous thromboembolism are major risk factors for stroke, disability, and death in the rapidly growing older (≥ 65 years.) population. In the absence of clear guidelines on the appropriate use of the newer non-vitamin K antagonist oral anticoagulants in this population, this study specifically reviews the available literature for rivaroxaban and the impact of age that may affect the pharmacokinetics, pharmacodynamics, efficacy, and safety of this anticoagulant. METHODS: This review includes a summary of data obtained from the available literature concerning both older healthy subjects and older patients with various aspects of cardiovascular disease enrolled in rivaroxaban clinical trials and data from real world evidence studies. RESULTS: Evaluation of the clinical pharmacology in healthy, older adults reveal no clinically relevant effect of age on rivaroxaban pharmacokinetics and pharmacodynamics. Population pharmacokinetic studies in older patients with thromboembolic diseases suggest a moderate effect of increasing age on rivaroxaban clearance, albeit not clinically significant. Additionally, sub-group analyses from large, phase 3 clinical trials demonstrate consistent efficacy and safety in the older patient population vs the overall population. These findings are further supported by real-world evidence studies. CONCLUSION: A favorable clinical profile with rivaroxaban was observed across age sub-groups, supporting the premise that dosing in older adults does not necessitate adjustment. However, it is prudent that a cautious and individualized approach is taken for treatment with any anticoagulant in older adults.


Subject(s)
Anticoagulants/therapeutic use , Rivaroxaban/therapeutic use , Aged , Atrial Fibrillation/drug therapy , Coronary Artery Disease/drug therapy , Humans , Risk Factors , Stroke/epidemiology , Venous Thromboembolism/drug therapy
6.
Mol Med Rep ; 16(4): 5441-5449, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28849216

ABSTRACT

Previous studies have reported that angelicin exerted antiproliferative effects on several types of tumor cell. However, to the best of our knowledge, the effects of angelicin monotherapy on human liver cancer remain to be investigated. In the present study, the antitumor activity of angelicin was evaluated in vitro and in vivo, and the molecular mechanisms underlying its effects were investigated. The present results revealed that angelicin induced apoptosis in liver cancer cells in a dose­ and time­dependent manner. Furthermore, in HepG2 and Huh­7 cells, angelicin­induced apoptosis was demonstrated to be mitochondria dependent, involving the phosphatidylinositol­4,5­bisphosphate 3­kinase/RAC­α serine/threonine-protein kinase signaling pathway. In addition, administration of angelicin to mice bearing liver tumor xenografts inhibited tumor growth, without producing significant secondary adverse effects. These results suggested that angelicin may have potential as a novel therapeutic agent for the treatment of patients with liver cancer.


Subject(s)
Antineoplastic Agents/pharmacology , Furocoumarins/pharmacology , Liver Neoplasms/pathology , Animals , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Caspase 3/metabolism , Caspase 9/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival , Disease Models, Animal , Dose-Response Relationship, Drug , Furocoumarins/chemistry , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/metabolism , Male , Mice , Mitochondria/drug effects , Mitochondria/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Xenograft Model Antitumor Assays
7.
J Stroke Cerebrovasc Dis ; 26(8): 1721-1731, 2017 Aug.
Article in English | MEDLINE | ID: mdl-28392100

ABSTRACT

BACKGROUND: Stroke mainly occurs in patients without atrial fibrillation (AF). This study explored risk prediction models for ischemic stroke and transient ischemic attack (TIA) in patients without AF. METHODS: Three US-based healthcare databases (Truven MarketScan Commercial Claims and Encounters [CCAE], Medicare Supplemental [MDCR], and Optum Clinformatics [Optum]) were used to establish patient cohorts without AF during the index period of 2008-2012. The performance of 2 existing models (CHADS2 and CHA2DS2-VASc) for predicting stroke and TIA was examined by fitting a logistic regression to a training dataset and evaluating predictive accuracy in a validation dataset (area under the curve, AUC) using patients with complete follow-up of 1 or 3 years, separately. RESULTS: The commercial populations were younger and had fewer comorbidities than Medicare-eligible population. The incidence proportions of ischemic stroke and TIA during 1 and 3 years of follow-up were .5% and 1.9% (CCAE), .6% and 2.2% (Optum), and 4.6% and 13.1% (MDCR), respectively. The models performed consistently across all 3 databases, with the AUC ranging from .69 to .77 and from .68 to .73 for 1- and 3-year prediction, respectively. Predictive accuracy was lower than the initial work of CHADS2 evaluation in patients with AF (AUC: .82), but consistent with a subsequent meta-analysis of CHADS2 (.60-.80) and CHA2DS2-VASc performance (.64-.79). CONCLUSION: Although the existing schemes for predicting ischemic stroke and TIA in patients with AF can be applied to patients without AF with comparable predictive accuracy, the evidence suggests that there is room for improvement in these models' performance.


Subject(s)
Brain Ischemia/epidemiology , Decision Support Techniques , Ischemic Attack, Transient/epidemiology , Stroke/epidemiology , Adult , Aged , Area Under Curve , Brain Ischemia/diagnosis , Comorbidity , Databases, Factual , Female , Humans , Incidence , Ischemic Attack, Transient/diagnosis , Logistic Models , Male , Medicare Part B , Middle Aged , Predictive Value of Tests , Prognosis , ROC Curve , Reproducibility of Results , Risk Assessment , Risk Factors , Stroke/diagnosis , Time Factors , United States/epidemiology
8.
Bioorg Med Chem Lett ; 26(19): 4625-4630, 2016 10 01.
Article in English | MEDLINE | ID: mdl-27592744

ABSTRACT

Previous efforts from our laboratory demonstrated that (E)-3-((3-(E)-vinylaryl)-1H-indazol-6-yl)methylene)-indolin-2-ones are potent PLK4 inhibitors with in vivo anticancer efficacy upon IP dosing. As part of a continued effort to develop selective and orally efficacious inhibitors, we examined variations on this theme wherein 'directly-linked' aromatics, pendant from the indazole core, replace the arylvinyl moiety. Herein, we describe the design and optimization of this series which was ultimately superseded by (3-aryl-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones. The latter compounds are potent and selective inhibitors of PLK4 with oral exposure in rodents and in vivo anticancer activity. Compound 13b, in particular, has a bioavailability of 22% and achieved a 96% tumor growth inhibition in an MDA-MB-468 xenograft study.


Subject(s)
Antineoplastic Agents/pharmacology , Indoles/chemistry , Indoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Area Under Curve , Cell Line, Tumor , Drug Design , Heterografts , Humans , Indoles/administration & dosage , Indoles/pharmacokinetics , Mice , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacokinetics , Rats
10.
Contemp Clin Trials ; 45(Pt B): 239-243, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26388115

ABSTRACT

Planned and unplanned subgroup analyses of large clinical trials are frequently performed and the results are sometimes difficult to interpret. The source of a nominal significant finding may come from a true signal, variation of the clinical trial outcome or the observed data structure. Quantitative assessment is critical to the interpretation of the totality of the clinical data. In this article we provide a general framework to manage subgroup analyses and to interpret the findings through a set of supplement analyses to planned main (primary and secondary) analyses, as an alternative to the commonly used multiple comparison framework. The proposed approach collectively and coherently utilizes several quantitative methods and enhances the credibility and interpretability of subgroup analyses. A case study is used to illustrate the application of the proposed method.


Subject(s)
Clinical Trials as Topic/methods , Data Interpretation, Statistical , Multicenter Studies as Topic/methods , Research Design , Clinical Trials, Phase III as Topic , Clinical Trials, Phase IV as Topic , Humans
11.
J Med Chem ; 58(1): 147-69, 2015 Jan 08.
Article in English | MEDLINE | ID: mdl-25723005

ABSTRACT

Previous publications from our laboratory have introduced novel inhibitors of Polo-like kinase 4 (PLK4), a mitotic kinase identified as a potential target for cancer therapy. The search for potent and selective PLK4 inhibitors yielded (E)-3-((1Hindazol-6-yl)methylene)indolin-2-ones, which were superseded by the bioisosteric 2-(1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones, e.g., 3. The later scaffold confers improved drug-like properties and incorporates two stereogenic centers. This work reports the discovery of a novel one-pot double SN2 displacement reaction for the stereoselective installation of the desired asymmetric centers and confirms the stereochemistry of the most potent stereoisomer, e.g., 44. Subsequent work keys on the optimization of the oral exposure of nanomolar PLK4 inhibitors with potent cancer cell growth inhibitory activity. A short list of compounds with superior potency and pharmacokinetic properties in rodents and dogs was studied in mouse models of tumor growth. We conclude with the identification of compound 48 (designated CFI-400945) as a novel clinical candidate for cancer therapy.


Subject(s)
Antineoplastic Agents/pharmacology , Indazoles/pharmacology , Indoles/pharmacology , Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/analysis , Administration, Oral , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Biological Availability , Cell Line, Tumor , Cell Survival/drug effects , Dogs , Dose-Response Relationship, Drug , Drug Discovery , Female , HCT116 Cells , Humans , Indazoles/chemistry , Indazoles/pharmacokinetics , Indoles/chemistry , Indoles/pharmacokinetics , MCF-7 Cells , Male , Mice, Nude , Mice, SCID , Models, Chemical , Molecular Structure , Neoplasms/metabolism , Neoplasms/pathology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/metabolism , Rats , Structure-Activity Relationship , Xenograft Model Antitumor Assays
12.
J Med Chem ; 58(1): 130-46, 2015 Jan 08.
Article in English | MEDLINE | ID: mdl-24867403

ABSTRACT

Polo-like kinase 4 (PLK4), a unique member of the polo-like kinase family of serine-threonine kinases, is a master regulator of centriole duplication that is important for maintaining genome integrity. Overexpression of PLK4 is found in several human cancers and is linked with a predisposition to tumorigenesis. Previous efforts to identify potent and efficacious PLK4 inhibitors resulted in the discovery of (E)-3-((1H-indazol-6-yl)methylene)indolin-2-ones, which are superseded by the bioisosteric 2-(1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones reported herein. Optimization of this new cyclopropane-linked series was based on a computational model of a PLK4 X-ray structure and SAR attained from the analogous alkenelinked series. The racemic cyclopropane-linked compounds showed PLK4 affinity and antiproliferative activity comparable to their alkene-linked congeners with improved hysicochemical, ADME, and pharmacokinetic properties. Positive xenograft results from the MDA-MB-468 human breast cancer xenograft model for compound 18 support the investigation of PLK4 inhibitors as anticancer therapeutics. A PLK4 X-ray co-structure with racemate 18 revealed preferential binding of the 1R,2S enantiomer to the PLK4 kinase domain.


Subject(s)
Antineoplastic Agents/pharmacology , Indoles/pharmacology , Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Spiro Compounds/pharmacology , Administration, Oral , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Biological Availability , Cell Line, Tumor , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Design , Drug Discovery , Drug Screening Assays, Antitumor , HCT116 Cells , Humans , Indoles/chemistry , Indoles/pharmacokinetics , MCF-7 Cells , Mice , Models, Chemical , Molecular Structure , Neoplasms/metabolism , Neoplasms/pathology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/metabolism , Rats , Spiro Compounds/chemistry , Spiro Compounds/pharmacokinetics , Structure-Activity Relationship , Xenograft Model Antitumor Assays
13.
ACS Chem Biol ; 9(10): 2263-73, 2014 Oct 17.
Article in English | MEDLINE | ID: mdl-25140871

ABSTRACT

The ebolaviruses cause severe and rapidly progressing hemorrhagic fever. There are five ebolavirus species; although much is known about Zaire ebolavirus (EBOV) and its neutralization by antibodies, little is known about Sudan ebolavirus (SUDV), which is emerging with increasing frequency. Here we describe monoclonal antibodies containing a human framework that potently inhibit infection by SUDV and protect mice from lethal challenge. The murine antibody 16F6, which binds the SUDV envelope glycoprotein (GP), served as the starting point for design. Sequence and structural alignment revealed similarities between 16F6 and YADS1, a synthetic antibody with a humanized scaffold. A focused phage library was constructed and screened to impart 16F6-like recognition properties onto the YADS1 scaffold. A panel of 17 antibodies were characterized and found to have a range of neutralization potentials against a pseudotype virus infection model. Neutralization correlated with GP binding as determined by ELISA. Two of these clones, E10 and F4, potently inhibited authentic SUDV and conferred protection and memory immunity in mice from lethal SUDV challenge. E10 and F4 were further shown to bind to the same epitope on GP as 16F6 with comparable affinities. These antibodies represent strong immunotherapeutic candidates for treatment of SUDV infection.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies/administration & dosage , Antigens, Viral/immunology , Ebolavirus/pathogenicity , Hemorrhagic Fever, Ebola/prevention & control , Receptors, Interferon/physiology , Viral Envelope Proteins/immunology , Amino Acid Sequence , Animals , Antibodies/chemistry , Antibodies/immunology , Antibodies, Neutralizing/chemistry , Antigens, Viral/chemistry , Ebolavirus/immunology , Enzyme-Linked Immunosorbent Assay , Epitopes/immunology , Female , Hemorrhagic Fever, Ebola/immunology , Hemorrhagic Fever, Ebola/virology , Humans , Male , Mice , Mice, Knockout , Molecular Sequence Data , Peptide Library , Protein Conformation , Sequence Homology, Amino Acid , Sudan
14.
Bioorg Med Chem ; 22(17): 4968-97, 2014 Sep 01.
Article in English | MEDLINE | ID: mdl-25043312

ABSTRACT

TTK kinase was identified by in-house siRNA screen and pursued as a tractable, novel target for cancer treatment. A screening campaign and systematic optimization, supported by computer modeling led to an indazole core with key sulfamoylphenyl and acetamido moieties at positions 3 and 5, respectively, establishing a novel chemical class culminating in identification of 72 (CFI-400936). This potent inhibitor of TTK (IC50=3.6nM) demonstrated good activity in cell based assay and selectivity against a panel of human kinases. A co-complex TTK X-ray crystal structure and results of a xenograft study with TTK inhibitors from this class are described.


Subject(s)
Amides/pharmacology , Benzeneacetamides/pharmacology , Cell Cycle Proteins/antagonists & inhibitors , Drug Discovery , Indazoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Amides/chemical synthesis , Amides/chemistry , Benzeneacetamides/chemical synthesis , Benzeneacetamides/chemistry , Cell Cycle Proteins/metabolism , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Indazoles/chemical synthesis , Indazoles/chemistry , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/metabolism , Protein-Tyrosine Kinases/metabolism , Structure-Activity Relationship
15.
Cancer Cell ; 26(2): 163-76, 2014 Aug 11.
Article in English | MEDLINE | ID: mdl-25043604

ABSTRACT

PLK4 was identified as a promising therapeutic target through a systematic approach that combined RNAi screening with gene expression analysis in human breast cancers and cell lines. A drug discovery program culminated in CFI-400945, a potent and selective PLK4 inhibitor. Cancer cells treated with CFI-400945 exhibit effects consistent with PLK4 kinase inhibition, including dysregulated centriole duplication, mitotic defects, and cell death. Oral administration of CFI-400945 to mice bearing human cancer xenografts results in the significant inhibition of tumor growth at doses that are well tolerated. Increased antitumor activity in vivo was observed in PTEN-deficient compared to PTEN wild-type cancer xenografts. Our findings provide a rationale for the clinical evaluation of CFI-400945 in patients with solid tumors, in particular those deficient in PTEN.


Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/enzymology , Indazoles/pharmacology , Indoles/pharmacology , Protein Serine-Threonine Kinases/metabolism , Animals , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Survival , Centrioles/drug effects , Centrioles/metabolism , Female , Gene Expression , Gene Knockdown Techniques , Humans , Inhibitory Concentration 50 , Mice , Mice, Inbred NOD , Mice, Nude , Mice, SCID , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/genetics , Tumor Burden/drug effects , Xenograft Model Antitumor Assays
16.
Inorg Chem ; 53(3): 1521-9, 2014 Feb 03.
Article in English | MEDLINE | ID: mdl-24422491

ABSTRACT

Nanocage structures derived from decasulfonated ß-cyclodextrin (SCD) intercalated ZnAl- and MgAl- layered double hydroxides (LDHs) were prepared through calcination-rehydration reactions. The ZnAl- and MgAl-LDH layers revealed different basal spacings (1.51 nm for SCD-ZnAl-LDH and 1.61 nm for SCD-MgAl-LDH) when contacting SCD, while producing similar monolayer and vertical SCD orientations with cavity axis perpendicular to the LDH layer. The structures of the SCD-LDH and carboxymethyl-ß-cyclodextrin (CMCD)-LDH intercalates were fully analyzed and compared, and a structural model for the SCD-LDH was proposed. The thermal stability of SCD after intercalation was remarkably enhanced, with decomposition temperature increased by 230 °C. The adsorption property of the SCD-LDH composites for phenol compounds (the effects of adsorption time and phenol concentration on adsorption) was investigated completely. The monolayer arrangement of the interlayer SCD did not affect the adsorption efficiency toward organic compounds, which verified the highly swelling ability of the layered compounds in solvents. Both composites illustrated preferential adsorptive efficiency for 2,3-dimethylphenol (DMP) in comparison with other two phenols of hydroquinone (HQ) and tert-butyl-phenol (TBP), resulting from appropriate hydrophobicity and steric hindrance of DMP. For the two phenols of HQ and TBP, SCD-MgAl-LDH gave better adsorption capacity compared with SCD-ZnAl-LDH. The double-confinement effect due to the combination of the parent LDH host and intercalated secondary host may impose high selectivity for guests. This kind of nanocage structure may have potential applications as adsorbents, synergistic agents, and storage vessels for particular guests.

17.
ACS Appl Mater Interfaces ; 5(23): 12716-24, 2013 Dec 11.
Article in English | MEDLINE | ID: mdl-24266516

ABSTRACT

Cobalt is a promising soft metallic magnetic material used for important applications in the field of absorbing stealth technology, especially for absorbing centimeter waves. However, it frequently presents a weak dielectric property because of its instability, aggregation, and crystallographic form. A method for enhancing the electromagnetic property of metal Co via phase-controlled synthesis of Co nanostructures grown on graphene (GN) networks has been developed. Hexagonal close-packed cobalt (α-Co) nanocrystals and face-centered cubic cobalt (ß-Co) nanospheres with uniform size and high dispersion have been successfully assembled on GN nanosheets via a facile one-step solution-phase strategy under different reaction conditions in which the exfoliated graphite oxide (graphene oxide, GO) nanosheets were reduced along with the formation of Co nanocrystals. The as-synthesized Co/GN nanocomposites showed excellent microwave absorbability in comparison with the corresponding Co nanocrystals or GN, especially for the nanocomposites of GN and α-Co nanocrystals (the reflection loss is -47.5 dB at 11.9 GHz), which was probably because of the special electrical properties of the cross-linked GN nanosheets and the perfect electromagnetic match in their microstructure as well as the small particle size of Co nanocrystals. The approach is convenient and effective. Some magnetic metal or alloy materials can also be prepared via this route because of its versatility.

18.
J Med Chem ; 56(15): 6069-87, 2013 Aug 08.
Article in English | MEDLINE | ID: mdl-23829549

ABSTRACT

The family of Polo-like kinases is important in the regulation of mitotic progression; this work keys on one member, namely Polo-like kinase 4 (PLK4). PLK4 has been identified as a candidate anticancer target which prompted a search for potent and selective inhibitors of PLK4. The body of the paper describes lead generation and optimization work which yielded nanomolar PLK4 inhibitors. Lead generation began with directed virtual screening, using a ligand-based focused library and a PLK4 homology model. Validated hits were used as starting points for the design and discovery of PLK4 inhibitors of novel structure, namely (E)-3-((1H-indazol-6-yl)methylene)indolin-2-ones. Computational models, based on a published X-ray structure (PLK4 kinase domain), were used to understand and optimize the in vitro activity of the series; potent antiproliferative activity was obtained. The kinase selectivity profile and cell cycle analysis of selected inhibitors are described. The results of a xenograft study with an optimized compound 50 (designated CFI-400437) support the potential of these novel PLK4 inhibitors for cancer therapy.


Subject(s)
Antineoplastic Agents/chemical synthesis , Indazoles/chemical synthesis , Indoles/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Female , Indazoles/chemistry , Indazoles/pharmacology , Indoles/chemistry , Indoles/pharmacology , Mice , Mice, SCID , Models, Molecular , Stereoisomerism , Structure-Activity Relationship , Transplantation, Heterologous
19.
J Control Release ; 172(2): 395-404, 2013 Dec 10.
Article in English | MEDLINE | ID: mdl-23880472

ABSTRACT

Humanized monoclonal antibodies (mAb) against HER2 are being engineered to treat cancer. We utilized phage-display technology to generate a novel anti-HER2 mAb (named 73JIgG) that binds an epitope of HER2 distinct from that of trastuzumab. Although these mAbs bind to the same cell surface receptor, they have different cell distribution profiles. After 3h of incubation, almost 10% of the total 73JIgG reaches the lysosome compared to less than 3% of trastuzumab. Interestingly, 73JIgG disassociates from HER2 whereas trastuzumab remains bound to the receptor. Importantly, HER2 distribution is not affected by the antibody binding epitope, thus negating this mechanism as the reason for the difference in intracellular trafficking of 73JIgG versus trastuzumab. Each of trastuzumab and 73JIgG was chemically-modified with either a small molecule or polymeric nanoparticle to better understand the influence of conjugation on cellular localization. Relative to antibody alone, antibody-nanoparticle conjugates resulted in a higher concentration of antibodies in the lysosome whereas antibody-small molecule conjugates did not affect cell trafficking to the lysosome. Given the importance of lysosomal targeting, these results demonstrate the importance of understanding the influence of the antibody-conjugate on cell trafficking for ultimate optimization of treatment selection.


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Breast Neoplasms/immunology , Drug Delivery Systems , Immunoconjugates/administration & dosage , Nanoparticles/chemistry , Receptor, ErbB-2/immunology , Amino Acid Sequence , Animals , Antibodies, Monoclonal, Humanized/chemistry , Antibodies, Monoclonal, Humanized/immunology , Antibodies, Monoclonal, Humanized/pharmacokinetics , Binding Sites, Antibody , Cell Line , Cell Line, Tumor , Drug Carriers/chemistry , Female , Humans , Immunoconjugates/chemistry , Immunoconjugates/immunology , Immunoconjugates/pharmacokinetics , Lysosomes/metabolism , Molecular Sequence Data , Peptide Library , Trastuzumab
20.
Ann N Y Acad Sci ; 1291: 42-55, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23701516

ABSTRACT

The development of rivaroxaban (XARELTO®) is an important new medical advance in the field of oral anticoagulation. Thrombosis-mediated conditions constitute a major burden for patients, healthcare systems, and society. For more than 60 years, the prevention and treatment of these conditions have been dominated by oral vitamin K antagonists (such as warfarin) and the injectable heparins. Thrombosis can lead to several conditions, including deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, and/or death. Prevention and treatment of thrombosis with an effective, convenient-to-use oral anticoagulant with a favorable safety profile is critical, especially in an aging society in which the risk of thrombosis, and the potential for bleeding complications, is increasing. Rivaroxaban acts to prevent and treat thrombosis by potently inhibiting coagulation Factor Xa in the blood. Factor Xa converts prothrombin to thrombin, which initiates the formation of blood clots by converting fibrinogen to clot-forming fibrin and leads to platelet activation. After a large and novel clinical development program in over 75,000 patients to date, rivaroxaban has received approval for multiple indications in the United States, European Union, and other countries worldwide to prevent and treat several thrombosis-mediated conditions. This review will highlight some of the unique aspects of the rivaroxaban development program.


Subject(s)
Anticoagulants/administration & dosage , Factor Xa Inhibitors , Morpholines/administration & dosage , Thiophenes/administration & dosage , Thrombosis/drug therapy , Administration, Oral , Animals , Anticoagulants/pharmacokinetics , Atrial Fibrillation/drug therapy , Atrial Fibrillation/epidemiology , Atrial Fibrillation/metabolism , Factor Xa/metabolism , Humans , Morpholines/pharmacokinetics , Rivaroxaban , Thiophenes/pharmacokinetics , Thrombosis/epidemiology , Thrombosis/metabolism , Treatment Outcome
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