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1.
Molecules ; 26(21)2021 Oct 30.
Article in English | MEDLINE | ID: mdl-34770981

ABSTRACT

Pim kinases (proviral integration site for Moloney murine leukemia virus kinases) are overexpressed in various types of hematological malignancies and solid carcinomas, and promote cell proliferation and survival. Thus, Pim kinases are validated as targets for antitumor therapy. In this context, our combined efforts in natural product-inspired library generation and screening furnished very promising dibenzo[b,d]furan derivatives derived from cercosporamide. Among them, lead compound 44 was highlighted as a potent Pim-1/2 kinases inhibitor with an additional nanomolar IC50 value against CLK1 (cdc2-like kinases 1) and displayed a low micromolar anticancer potency towards the MV4-11 (AML) cell line, expressing high endogenous levels of Pim-1/2 kinases. The design, synthesis, structure-activity relationship, and docking studies are reported herein and supported by enzyme, cellular assays, and Galleria mellonella larvae testing for acute toxicity.


Subject(s)
Antineoplastic Agents/pharmacology , Benzofurans/chemistry , Benzofurans/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzofurans/chemical synthesis , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Humans , Models, Molecular , Molecular Structure , Moths , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/metabolism , Protein-Tyrosine Kinases/metabolism , Proto-Oncogene Proteins c-pim-1/metabolism , Tumor Cells, Cultured
2.
Arch Pharm (Weinheim) ; 354(8): e2000450, 2021 Aug.
Article in English | MEDLINE | ID: mdl-33852185

ABSTRACT

Current multiagent chemotherapy regimens have improved the cure rate in acute leukemia patients, but they are highly toxic and poorly efficient in relapsed patients. To improve the treatment approaches, new specific molecules are needed. The G-quadruplexes (G4s), which are noncanonical nucleic acid structures found in specific guanine-rich DNA or RNA, are involved in many cellular events, including control of gene expression. G4s are considered as targets for the development of anticancer agents. Heterocyclic molecules are well known to target and stabilize G4 structures. Thus, a new series of 2,9-bis[(substituted-aminomethyl)phenyl]-1,10-phenanthroline derivatives (1a-i) was designed, synthesized, and evaluated against five human myeloid leukemia cell lines (K562, KU812, MV4-11, HL60, and U937). Their ability to stabilize various oncogene promoter G4 structures (c-MYC, BCL-2, and K-RAS) as well as the telomeric G4 was also determined through the fluorescence resonance energy transfer melting assay and native mass spectrometry. In addition, the more bioactive ligands 1g-i were tested for telomerase activity in HuT78 and MV4-11 protein extracts.


Subject(s)
Antineoplastic Agents/pharmacology , Leukemia, Myeloid, Acute/drug therapy , Phenanthrolines/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Drug Design , Fluorescence Resonance Energy Transfer , G-Quadruplexes/drug effects , HL-60 Cells , Humans , K562 Cells , Leukemia, Myeloid, Acute/pathology , Ligands , Phenanthrolines/chemical synthesis , Phenanthrolines/chemistry , Structure-Activity Relationship , Telomerase/metabolism , U937 Cells
3.
Molecules ; 26(4)2021 Feb 06.
Article in English | MEDLINE | ID: mdl-33562106

ABSTRACT

Proviral integration site for Moloney murine leukemia virus (Pim)-1/2 kinase overexpression has been identified in a variety of hematologic (e.g., multiple myeloma or acute myeloid leukemia (AML)) and solid (e.g., colorectal carcinoma) tumors, playing a key role in cancer progression, metastasis, and drug resistance, and is linked to poor prognosis. These kinases are thus considered interesting targets in oncology. We report herein the design, synthesis, structure-activity relationships (SAR) and in vitro evaluations of new quinoxaline derivatives, acting as dual Pim1/2 inhibitors. Two lead compounds (5c and 5e) were then identified, as potent submicromolar Pim-1 and Pim-2 inhibitors. These molecules were also able to inhibit the growth of the two human cell lines, MV4-11 (AML) and HCT-116 (colorectal carcinoma), expressing high endogenous levels of Pim-1/2 kinases.


Subject(s)
Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Quinoxalines/chemical synthesis , Quinoxalines/pharmacology , Chemistry Techniques, Synthetic , Humans , Molecular Docking Simulation , Protein Conformation , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/chemistry , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-pim-1/chemistry , Proto-Oncogene Proteins c-pim-1/metabolism , Quinoxalines/chemistry , Quinoxalines/metabolism
4.
ChemMedChem ; 16(6): 1034-1046, 2021 03 18.
Article in English | MEDLINE | ID: mdl-33275308

ABSTRACT

Signal transducers and activators of transcription 5A and 5B (STAT5A and STAT5B) are two closely related STAT family members that are crucial downstream effectors of tyrosine kinase oncoproteins such as FLT3-ITD in acute myeloid leukemia (AML) and BCR-ABL in chronic myeloid leukemia (CML). We recently developed and reported the synthesis of a first molecule called 17 f that selectively inhibits STAT5 signaling in myeloid leukemia cells and overcomes their resistance to chemotherapeutic agents. To improve the antileukemic effect of 17 f, we synthesized ten analogs of this molecule and analyzed their impact on cell growth, survival, chemoresistance and STAT5 signaling. Two compounds, 7 a and 7 a', were identified as having similar or higher antileukemic effects in various AML and CML cell lines. Both molecules were found to be more effective than 17 f at inhibiting STAT5 activity/expression and suppressing the chemoresistance of CML.


Subject(s)
Antineoplastic Agents/pharmacology , Leukemia, Myeloid/drug therapy , Quinolines/pharmacology , STAT5 Transcription Factor/antagonists & inhibitors , Tumor Suppressor Proteins/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Leukemia, Myeloid/metabolism , Leukemia, Myeloid/pathology , Molecular Structure , Quinolines/chemical synthesis , Quinolines/chemistry , STAT5 Transcription Factor/metabolism , Signal Transduction/drug effects , Structure-Activity Relationship , Tumor Suppressor Proteins/metabolism
5.
J Cell Mol Med ; 24(17): 10052-10062, 2020 09.
Article in English | MEDLINE | ID: mdl-32667731

ABSTRACT

Acriflavine (ACF) is an antiseptic with anticancer properties, blocking the growth of solid and haematopoietic tumour cells. Moreover, this compound has been also shown to overcome the resistance of cancer cells to chemotherapeutic agents. ACF has been shown to target hypoxia-inducible factors (HIFs) activity, which are key effectors of hypoxia-mediated chemoresistance. In this study, we showed that ACF inhibits the growth and survival of chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML) cell lines in normoxic conditions. We further demonstrated that ACF down-regulates STAT5 expression in CML and AML cells but activates STAT3 in CML cells in a HIF-independent manner. In addition, we demonstrated that ACF suppresses the resistance of CML cells to tyrosine kinase inhibitors, such as imatinib. Our data suggest that the dual effect of ACF might be exploited to eradicate de novo or acquired resistance of myeloid leukaemia cells to chemotherapy.


Subject(s)
Acriflavine/pharmacology , Carcinogenesis/drug effects , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , STAT5 Transcription Factor/genetics , Signal Transduction/drug effects , Tumor Suppressor Proteins/genetics , Antineoplastic Agents/pharmacology , Carcinogenesis/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/genetics , Down-Regulation/drug effects , Down-Regulation/genetics , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Humans , K562 Cells , Protein Kinase Inhibitors/pharmacology
6.
Immunol Res ; 68(1): 7-12, 2020 02.
Article in English | MEDLINE | ID: mdl-32144721

ABSTRACT

During World War I (WWI), infectious diseases including tetanus were among the most important causes of death. Even though its efficacy was somewhat controversial before the war, tetanus antiserum played a key role in reducing the mortality of this disease. A vial of tetanus antiserum dating back from WWI, left behind on the French battlefield by the US Army, was borrowed from a private collection and opened. The serum contained within was characterized by orthogonal biochemical techniques to determine if any neutralizing IgGs could remain after 100 years of storage. In vitro analysis by Size Exclusion Chromatography and Serum Protein Electrophoresis suggested the presence of residual IgG. In spite of our hopes, these IgGs were not able to protect mice against tetanus toxin challenge in a neutralizing assay. Even though our results indicate the presence of remaining IgGs inside the serum, they were functionally disabled. These results show that obscurity alone is insufficient to protect IgGs from degradation over very long periods of time at room temperature. HIGHLIGHTS: Tetanus antiserum found its place in the therapeutic arsenal during World War I A century-old vial of tetanus antiserum was opened for biochemical and in vivo characterization Biochemical assays revealed the presence of proteins having all the characteristics of IgGs The serum was unable to protect mice against toxinic challenge.


Subject(s)
Clostridium tetani/immunology , Immune Sera/analysis , Immunization, Passive/history , Immunoglobulin G/metabolism , Tetanus/immunology , Animals , Blood Protein Electrophoresis , Chromatography, Gel , History, 19th Century , History, 20th Century , History, 21st Century , Humans , Mice , Neutralization Tests , Tetanus Toxin/immunology , World War I
7.
Cancers (Basel) ; 12(1)2020 Jan 18.
Article in English | MEDLINE | ID: mdl-31963765

ABSTRACT

Signal Transducer and Activator of Transcription (STAT) 3 and 5 are important effectors of cellular transformation, and aberrant STAT3 and STAT5 signaling have been demonstrated in hematopoietic cancers. STAT3 and STAT5 are common targets for different tyrosine kinase oncogenes (TKOs). In addition, STAT3 and STAT5 proteins were shown to contain activating mutations in some rare but aggressive leukemias/lymphomas. Both proteins also contribute to drug resistance in hematopoietic malignancies and are now well recognized as major targets in cancer treatment. The development of inhibitors targeting STAT3 and STAT5 has been the subject of intense investigations during the last decade. This review summarizes the current knowledge of oncogenic STAT3 and STAT5 functions in hematopoietic cancers as well as advances in preclinical and clinical development of pharmacological inhibitors.

8.
Immunol Res, v. 68, p. 7-12, mar. 2020
Article in English | Sec. Est. Saúde SP, SESSP-IBPROD, Sec. Est. Saúde SP | ID: bud-2967

ABSTRACT

During World War I (WWI), infectious diseases including tetanus were among the most important causes of death. Even though its efficacy was somewhat controversial before the war, tetanus antiserum played a key role in reducing the mortality of this disease. A vial of tetanus antiserum dating back from WWI, left behind on the French battlefield by the US Army, was borrowed from a private collection and opened. The serum contained within was characterized by orthogonal biochemical techniques to determine if any neutralizing IgGs could remain after 100 years of storage. In vitro analysis by Size Exclusion Chromatography and Serum Protein Electrophoresis suggested the presence of residual IgG. In spite of our hopes, these IgGs were not able to protect mice against tetanus toxin challenge in a neutralizing assay. Even though our results indicate the presence of remaining IgGs inside the serum, they were functionally disabled. These results show that obscurity alone is insufficient to protect IgGs from degradation over very long periods of time at room temperature.

9.
Immunol. Res. ; 68: 7-12, 2020.
Article in English | Sec. Est. Saúde SP, SESSP-IBPROD, Sec. Est. Saúde SP | ID: but-ib17524

ABSTRACT

During World War I (WWI), infectious diseases including tetanus were among the most important causes of death. Even though its efficacy was somewhat controversial before the war, tetanus antiserum played a key role in reducing the mortality of this disease. A vial of tetanus antiserum dating back from WWI, left behind on the French battlefield by the US Army, was borrowed from a private collection and opened. The serum contained within was characterized by orthogonal biochemical techniques to determine if any neutralizing IgGs could remain after 100 years of storage. In vitro analysis by Size Exclusion Chromatography and Serum Protein Electrophoresis suggested the presence of residual IgG. In spite of our hopes, these IgGs were not able to protect mice against tetanus toxin challenge in a neutralizing assay. Even though our results indicate the presence of remaining IgGs inside the serum, they were functionally disabled. These results show that obscurity alone is insufficient to protect IgGs from degradation over very long periods of time at room temperature.

10.
Cancers (Basel) ; 11(12)2019 Dec 17.
Article in English | MEDLINE | ID: mdl-31861239

ABSTRACT

Signal transducers and activators of transcription 5A and 5B (STAT5A and STAT5B) are crucial downstream effectors of tyrosine kinase oncogenes (TKO) such as BCR-ABL in chronic myeloid leukemia (CML) and FLT3-ITD in acute myeloid leukemia (AML). Both proteins have been shown to promote the resistance of CML cells to tyrosine kinase inhibitors (TKI) such as imatinib mesylate (IM). We recently synthesized and discovered a new inhibitor (17f) with promising antileukemic activity. 17f selectively inhibits STAT5 signaling in CML and AML cells by interfering with the phosphorylation and transcriptional activity of these proteins. In this study, the effects of 17f were evaluated on CML and AML cell lines that respectively acquired resistance to IM and cytarabine (Ara-C), a conventional therapeutic agent used in AML treatment. We showed that 17f strongly inhibits the growth and survival of resistant CML and AML cells when associated with IM or Ara-C. We also obtained evidence that 17f inhibits STAT5B but not STAT5A protein expression in resistant CML and AML cells. Furthermore, we demonstrated that 17f also targets oncogenic STAT5B N642H mutant in transformed hematopoietic cells.

11.
Eur J Med Chem ; 154: 101-109, 2018 Jun 25.
Article in English | MEDLINE | ID: mdl-29778892

ABSTRACT

We identified a new series of quinoxaline-2-carboxylic acid derivatives, targeting the human proviral integration site for Moloney murine leukemia virus-1 (HsPim-1) kinase. Seventeen analogues were synthesized providing useful insight into structure-activity relationships studied. Docking studies realized in the ATP pocket of HsPim-1 are consistent with an unclassical binding mode of these inhibitors. The lead compound 1 was able to block HsPim-1 enzymatic activity at nanomolar concentrations (IC50 of 74 nM), with a good selectivity profile against a panel of mammalian protein kinases. In vitro studies on the human chronic myeloid leukemia cell line KU812 showed an antitumor activity at micromolar concentrations. As a result, compound 1 represents a promising lead for the design of novel anticancer targeted therapies.


Subject(s)
Drug Design , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Quinoxalines/pharmacology , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-pim-1/metabolism , Quinoxalines/chemical synthesis , Quinoxalines/chemistry , Structure-Activity Relationship , Tumor Cells, Cultured
12.
Org Biomol Chem ; 16(11): 1882-1889, 2018 03 14.
Article in English | MEDLINE | ID: mdl-29473076

ABSTRACT

Herein we describe the synthesis and evaluation of four novel HER2-targeting, cathepsin B-sensitive antibody-drug conjugates bearing a monomethylauristatin E (MMAE) cytotoxic payload, constructed via the conjugation of cleavable linkers to trastuzumab using a site-specific bioconjugation methodology. These linkers vary by both cleavable trigger motif and hydrophilicity, containing one of two cathepsin B sensitive dipeptides (Val-Cit and Val-Ala), and engendered with either hydrophilic or hydrophobic character via application of a PEG12 spacer. Through evaluation of physical properties, in vitro cytotoxicity, and receptor affinity of the resulting antibody-drug conjugates (ADCs), we have demonstrated that while both dipeptide triggers are effective, the increased hydrophobicity of the Val-Ala pair limits its utility within this type of linker. In addition, while PEGylation augments linker hydrophilicity, this change does not translate to more favourable ADC hydrophilicity or potency. While all described structures demonstrated excellent and similar in vitro cytotoxicity, the ADC with the ValCitPABMMAE linker shows the most promising combination of in vitro potency, structural homogeneity, and hydrophilicity, warranting further evaluation into its therapeutic potential.


Subject(s)
Antineoplastic Agents, Immunological/chemistry , Cathepsin B/metabolism , Immunoconjugates/chemistry , Oligopeptides/chemistry , Receptor, ErbB-2/metabolism , Trastuzumab/chemistry , Antineoplastic Agents, Immunological/chemical synthesis , Antineoplastic Agents, Immunological/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Chemistry Techniques, Synthetic/methods , Drug Delivery Systems , Humans , Hydrophobic and Hydrophilic Interactions , Immunoconjugates/pharmacology , Neoplasms/drug therapy , Oligopeptides/chemical synthesis , Oligopeptides/pharmacology , Trastuzumab/pharmacology
13.
J Med Chem ; 60(14): 6119-6136, 2017 07 27.
Article in English | MEDLINE | ID: mdl-28654259

ABSTRACT

Signal transducers and activators of transcription 5 (STAT5s) are crucial effectors of tyrosine kinase oncogenes in myeloid leukemias. Inhibition of STAT5 would contribute to reducing the survival of leukemic cells and also tackling their chemoresistance. In a first screening experiment, we identified hit 13 as able to inhibit STAT5 phosphorylation and leukemic cell growth. The synthesis of 18 analogues of 13 allowed us to identify one compound, 17f, as having the most potent antileukemic effect. 17f inhibited the growth of acute and chronic myeloid leukemia cells and the phosphorylation and transcriptional activity of STAT5. Importantly, 17f had minimal effects on bone marrow stromal cells that play vital functions in the microenvironment of hematopoietic and leukemic cells. We also demonstrated that 17f inhibits STAT5 but not STAT3, AKT, or Erk1/2 phosphorylation. These results suggest that 17f might be a new lead molecule targeting STAT5 signaling in myeloid leukemias.


Subject(s)
Antineoplastic Agents/chemistry , Indoles/chemistry , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myeloid, Acute/drug therapy , Quinolines/chemistry , STAT5 Transcription Factor/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Humans , Indoles/chemical synthesis , Indoles/pharmacology , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Quinolines/chemical synthesis , Quinolines/pharmacology , Signal Transduction , Structure-Activity Relationship
14.
Oncotarget ; 8(26): 41876-41889, 2017 Jun 27.
Article in English | MEDLINE | ID: mdl-27566554

ABSTRACT

STAT5 transcription factors are frequently activated in hematopoietic neoplasms and are targets of various tyrosine kinase oncogenes. Evidences for a crosstalk between STAT5 and reactive oxygen species (ROS) metabolism have recently emerged but mechanisms involved in STAT5-mediated regulation of ROS still remain elusive. We demonstrate that sustained activation of STAT5 induced by Bcr-Abl in chronic myeloid leukemia (CML) cells promotes ROS production by repressing expression of two antioxidant enzymes, catalase and glutaredoxin-1(Glrx1). Downregulation of catalase and Glrx1 expression was also observed in primary cells from CML patients. Catalase was shown not only to reduce ROS levels but also, to induce quiescence in Bcr-Abl-positive leukemia cells. Furthermore, reduction of STAT5 phosphorylation and upregulation of catalase and Glrx1 were also evidenced in leukemia cells co-cultured with bone marrow stromal cells to mimic a leukemic niche. This caused downregulation of ROS levels and enhancement of leukemic cell quiescence. These data support a role of persistent STAT5 signaling in the regulation of ROS production in myeloid leukemias and highlight the repression of antioxidant defenses as an important regulatory mechanism.


Subject(s)
Antioxidants/metabolism , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Oxidative Stress , STAT5 Transcription Factor/metabolism , Signal Transduction , Catalase/metabolism , Cell Cycle Checkpoints/genetics , Cell Line, Tumor , Fusion Proteins, bcr-abl/genetics , Fusion Proteins, bcr-abl/metabolism , Glutaredoxins/genetics , Glutaredoxins/metabolism , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Models, Biological , Reactive Oxygen Species/metabolism
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