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2.
PLoS One ; 15(8): e0237030, 2020.
Article in English | MEDLINE | ID: mdl-32810141

ABSTRACT

Curative therapeutic options for a number of immunological disorders remain to be established, and approaches for identifying drug candidates are relatively limited. Furthermore, phenotypic screening methods using induced pluripotent stem cell (iPSC)-derived immune cells or hematopoietic cells need improvement. In the present study, using immortalized monocytic cell lines derived from iPSCs, we developed a high-throughput screening (HTS) system to detect compounds that inhibit IL-1ß secretion and NLRP3 inflammasome activation from activated macrophages. The iPSCs were generated from a patient with neonatal onset multisystem inflammatory disease (NOMID) as a model of a constitutively activated NLRP3 inflammasome. HTS of 4,825 compounds including FDA-approved drugs and compounds with known bioactivity identified 7 compounds as predominantly IL-1ß inhibitors. Since these compounds are known inflammasome inhibitors or derivatives of, these results prove the validity of our HTS system, which can be a versatile platform for identifying drug candidates for immunological disorders associated with monocytic lineage cells.


Subject(s)
High-Throughput Screening Assays/methods , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Carrier Proteins/metabolism , Caspase 1/metabolism , Cell Line , Cells, Cultured , Cryopyrin-Associated Periodic Syndromes/immunology , Cryopyrin-Associated Periodic Syndromes/physiopathology , Humans , Induced Pluripotent Stem Cells/metabolism , Inflammasomes/physiology , Inflammation/metabolism , Interleukin-1beta , Macrophages/metabolism , Monocytes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/physiology
4.
Leuk Res ; 38(5): 619-24, 2014 May.
Article in English | MEDLINE | ID: mdl-24679585

ABSTRACT

JAK2/STAT signaling promotes survival and expansion of myelodysplastic syndrome (MDS) clones, but little is known about the potential of JAK2/STAT as a therapeutic target in MDS. We investigated the effect of NS-018, a novel antagonist for JAK2, on the colony-forming ability of bone marrow mononuclear cells (BMMNCs) from high-risk MDS patients. NS-018 decreased colony-forming unit-granulocyte/macrophage (CFU-GM) colony numbers from MDS-derived BMMNCs in a dose-dependent manner, and this effect was significantly more potent than against normal BMMNCs. In addition, NS-018 suppressed the phosphorylation of STAT3 in colony-forming cells from MDS patients. Collectively, NS-018 could be a new therapeutic option for high-risk MDS.


Subject(s)
Bone Marrow Cells/physiology , Janus Kinase 2/antagonists & inhibitors , Myelodysplastic Syndromes/drug therapy , Protein Kinase Inhibitors/pharmacology , Stem Cells/drug effects , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Risk , STAT3 Transcription Factor/metabolism
5.
Anticancer Res ; 32(3): 795-8, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22399596

ABSTRACT

BACKGROUND: The myelodysplastic syndromes (MDS) are a group of stem cell disorders characterized by dysplasia of one or more hematopoietic cell lineages and a risk of progression to acute myeloid leukemia. The cytidine analog azacitidine (Vidaza), a hypomethylating agent, improves survival in patients with MDS, but its mechanism of action is not well understood. MATERIALS AND METHODS: The effects of azacitidine on the MDS-derived cell line SKM-1 were investigated by DNA methylation assay, cell proliferation assay, and a subcutaneous xenograft mouse model. RESULTS: Azacitidine and decitabine induced hypomethylation of the tumor suppressor gene cyclin-dependent kinase 4 inhibitor B (CDKN2B) in SKM-1 cells, whereas the deoxycytidine analog cytarabine did not. Azacitidine and decitabine also inhibited SKM-1 cell growth in vitro. In the mouse xenograft model, azacitidine significantly suppressed tumor growth. CONCLUSION: Inhibition of DNA methyltransferase by azacitidine contributes to its antiproliferative and antitumor effects against SKM-1 cells and may explain its clinical efficacy in MDS.


Subject(s)
Antineoplastic Agents/pharmacology , Azacitidine/pharmacology , Cell Proliferation/drug effects , Myelodysplastic Syndromes/pathology , Cell Line, Tumor , Cyclin-Dependent Kinase Inhibitor p15/genetics , DNA Methylation , Humans
6.
Bioorg Med Chem Lett ; 17(10): 2712-7, 2007 May 15.
Article in English | MEDLINE | ID: mdl-17376680

ABSTRACT

To investigate why 3-substituted benzamide derivatives show dual inhibition of Abl and Lyn protein tyrosine kinases, we determined their inhibitory activities against Abl and Lyn, carried out molecular modeling, and conducted a structure-activity relationship study with the aid of a newly determined X-ray structure of the Abl/Lyn dual inhibitor INNO-406 (formerly known as NS-187) bound to human Abl. We found that this series of compounds interacted with both kinases in very similar ways, so that they can inhibit both kinases effectively.


Subject(s)
Benzamides/pharmacology , Enzyme Inhibitors/pharmacology , Proto-Oncogene Proteins c-abl/antagonists & inhibitors , Pyrimidines/pharmacology , src-Family Kinases/antagonists & inhibitors , Benzamides/chemistry , Enzyme Inhibitors/chemistry , Humans , Molecular Conformation , Pyrimidines/chemistry , Structure-Activity Relationship
7.
J Biol Chem ; 282(17): 12963-75, 2007 Apr 27.
Article in English | MEDLINE | ID: mdl-17324926

ABSTRACT

Mannan-binding protein (MBP) is a C-type serum lectin that is an important constituent of the innate immune defense because it activates the complement system via the lectin pathway. While the pig has been proposed to be an attractive source of xenotransplantable tissues and organs, little is known about porcine MBP. In our previous studies, phosphomannan, but not mannan, was found to be an effective inhibitor of the C1q-independent bactericidal activity of newborn piglet serum against some rough strains of Gram-negative bacteria. In contrast, the inhibitory activities of phosphomannan and mannan were very similar in the case of MBP-dependent bactericidal activity against rough strains of Escherichia coli K-12 and S-16. Based on these findings, we inferred that an MBP-like lectin with slightly or completely different carbohydrate binding specificity might exist in newborn piglet serum and be responsible for the C1q-independent bactericidal activity. Herein we report that a novel phosphomannan-binding lectin (PMBL) of 33 kDa under reducing conditions was isolated from both newborn and adult porcine serum and characterized. Porcine PMBL functionally activated the complement system via the lectin pathway triggered by binding with both phosphomannan (P-mannan) and mannan, which, unlike MBP, was effectively inhibited by mannose 6-phosphate- or galatose-containing oligosaccharides. Our observations suggest that porcine PMBL plays a critical role in the innate immune defense from the newborn stage to adult-hood, and the establishment of a newborn piglet experimental model for the innate immune system studies is a valuable step toward elucidation of the physiological function and molecular mechanism of lectin pathway.


Subject(s)
Complement Pathway, Mannose-Binding Lectin/genetics , Immunity, Innate/genetics , Lectins, C-Type/genetics , Animals , Animals, Newborn , Base Sequence , Cloning, Molecular , Complement C1q/immunology , Escherichia coli K12/immunology , Lectins, C-Type/immunology , Lectins, C-Type/isolation & purification , Mannans/immunology , Molecular Sequence Data , Serum/chemistry , Serum/metabolism , Swine
8.
Leuk Res ; 30(11): 1443-6, 2006 Nov.
Article in English | MEDLINE | ID: mdl-16546254

ABSTRACT

Advanced-phase chronic myeloid leukemia patients treated with imatinib often relapse due to point mutations in the Abl kinase domain. We herein examine the in vitro and in vivo effects of a Bcr-Abl/Lyn dual tyrosine kinase inhibitor, NS-187, on seven mutated Bcr-Abl proteins. NS-187 inhibited both Tyr393-phosphorylated and Tyr393-unphosphorylated Abl, resulting in significant in vitro growth inhibition of cells expressing six of seven mutated Bcr-Abl kinases, though not T315I. Furthermore, NS-187 prolonged the survival of mice injected with leukemic cells expressing all mutated Bcr-Abl tested except T315I, and its efficacy correlated well with its in vitro effects.


Subject(s)
Fusion Proteins, bcr-abl/drug effects , Fusion Proteins, bcr-abl/genetics , Leukemia/drug therapy , Pyrimidines/administration & dosage , src-Family Kinases/antagonists & inhibitors , Administration, Oral , Animals , Benzamides , Cell Line, Tumor , Cell Proliferation/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Fusion Proteins, bcr-abl/metabolism , Humans , Imatinib Mesylate , Leukemia/genetics , Leukemia/metabolism , Mice , Mice, Inbred BALB C , Mice, Nude , Mutation , Phosphorylation , Piperazines/administration & dosage , Piperazines/pharmacology , Pyrimidines/pharmacology , Structure-Activity Relationship , Survival Rate , Transplantation, Heterologous , Xenograft Model Antitumor Assays
9.
Bioorg Med Chem Lett ; 16(5): 1421-5, 2006 Mar 01.
Article in English | MEDLINE | ID: mdl-16332440

ABSTRACT

A series of 3-substituted benzamide derivatives structurally related to STI-571 (imatinib mesylate), a Bcr-Abl tyrosine kinase inhibitor used to treat chronic myeloid leukemia (CML), was prepared and evaluated for antiproliferative activity against the Bcr-Abl-positive leukemia cell line K562. About ten 3-halogenated and 3-trifluoromethylated benzamide derivatives were identified as highly potent Bcr-Abl kinase inhibitors. One of these, NS-187 (9b), is a promising new candidate Bcr-Abl inhibitor for the therapy of STI-571-resistant chronic myeloid leukemia.


Subject(s)
Benzamides/chemistry , Benzamides/pharmacology , Drug Design , Fusion Proteins, bcr-abl/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Benzamides/chemical synthesis , Cell Line, Tumor , Cell Proliferation/drug effects , Fusion Proteins, bcr-abl/chemistry , Fusion Proteins, bcr-abl/metabolism , Humans , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemistry , Protein Structure, Tertiary , Structure-Activity Relationship
10.
Blood ; 106(12): 3948-54, 2005 Dec 01.
Article in English | MEDLINE | ID: mdl-16105974

ABSTRACT

Although the Abelson (Abl) tyrosine kinase inhibitor imatinib mesylate has improved the treatment of breakpoint cluster region-Abl (Bcr-Abl)-positive leukemia, resistance is often reported in patients with advanced-stage disease. Although several Src inhibitors are more effective than imatinib and simultaneously inhibit Lyn, whose overexpression is associated with imatinib resistance, these inhibitors are less specific than imatinib. We have identified a specific dual Abl-Lyn inhibitor, NS-187 (elsewhere described as CNS-9), which is 25 to 55 times more potent than imatinib in vitro. NS-187 is also at least 10 times as effective as imatinib in suppressing the growth of Bcr-Abl-bearing tumors and markedly extends the survival of mice bearing such tumors. The inhibitory effect of NS-187 extends to 12 of 13 Bcr-Abl proteins with mutations in their kinase domain but not to T315I. NS-187 also inhibits Lyn without affecting the phosphorylation of Src, Blk, or Yes. These results suggest that NS-187 may be a potentially valuable novel agent to combat imatinib-resistant Philadelphia-positive (Ph+) leukemia.


Subject(s)
Genes, abl/drug effects , Leukemia/drug therapy , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , src-Family Kinases/drug effects , Animals , Benzamides , Cell Line, Tumor , Drug Resistance, Neoplasm , Female , Genes, abl/genetics , Humans , Imatinib Mesylate , Mice , Mutation , Piperazines/therapeutic use , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Pyrimidines/therapeutic use
11.
Clin Cancer Res ; 10(22): 7721-6, 2004 Nov 15.
Article in English | MEDLINE | ID: mdl-15570006

ABSTRACT

PURPOSE: The RNA interference effect is an alternative to antisense DNA as an experimental method of down-regulating a specific target protein. Although the RNA interference effect, which is mediated by small interfering RNA (siRNA) or micro-RNA, has potential application to human therapy, the hydrodynamic method usually used for rapid administration of oligonucleotides is unsuitable for use in humans. In this study, we have investigated the antitumor activity of a synthetic siRNA, B717, which is sequence specific for the human bcl-2 oncogene, complexed with a novel cationic liposome, LIC-101. EXPERIMENTAL DESIGN: In a mouse model of liver metastasis, we administered B717/LIC-101 by bolus intravenous injection, adjusting the rate and volume of administration to what is feasible in human therapy. In a mouse model bearing prostate cancer in which the cells were inoculated under the skin, B717/LIC-101 was administered subcutaneously around the tumor. RESULTS: The B717/LIC-101 complex inhibited the expression of bcl-2 protein and the growth of tumor cell lines in vitro in a sequence-specific manner in the concentration range of 3 to 100 nmol/L. Furthermore, the complex had a strong antitumor activity when administered intravenously in the mouse model of liver metastasis. B717 (siRNA) was shown to be delivered to tumor cells in the mouse liver, but only when complexed with LIC-101. The complex also inhibited tumor cell growth in the mouse model bearing prostate cancer. CONCLUSIONS: By combining siRNA with our cationic liposome, we overcame the difficulty of administering siRNA to animals in ways that can be applied in human therapy. Although our siRNA/liposome complex is not yet in clinical trials, it is expected to provide a novel siRNA therapy for cancer patients.


Subject(s)
Antineoplastic Agents/pharmacology , Cations/chemistry , Liposomes/chemistry , Neoplasms/drug therapy , RNA, Small Interfering/chemistry , Animals , Blotting, Western , Cell Line, Tumor , DNA/chemistry , Disease Models, Animal , Dose-Response Relationship, Drug , Down-Regulation , Humans , Injections, Intravenous , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Metastasis , Neoplasms/genetics , Oligonucleotides/chemistry , Proto-Oncogene Proteins c-bcl-2/chemistry , RNA, Small Interfering/metabolism , Time Factors
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