Abstract:
:Scaffold-based analogs of cinnamic acid benzyl amide (CABA) exhibit pleiotropic effects in cancer cells, and their exact molecular mechanism of action is under investigation. The present study is part of our systemic analysis of interactions of CABA analogs with their molecular targets. These compounds were shown to inhibit Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) and JAK2/signal transducer and activator of transcription 5 (STAT5) signaling and thus are attractive scaffolds for anticancer drug design. To identify the potential mechanisms of action of this class of compounds, direct interactions of the selected CABA analogs with JAK2 kinase were examined. Inhibition of JAK2 enzymatic activity was assessed, and molecular modeling studies of selected compounds-(E)-2-cyano-N-[(S)-1-phenylethyl]-3-(pyridin-2-yl)acrylamide (WP1065), (E)-2-cyano-N-[(S)-1-phenylbutyl]- 3-(3-bromopyridin-2-yl)acrylamide (WP1130), and (E)-2-cyano-N-[(S)-1,4-diphenylbutyl]-3-(3-bromopyridin-2-yl)acrylamide (WP1702)-in the JAK2 kinase domain were used to support interpretation of the experimental data. Our results indicated that the tested CABA analogs are nonclassical inhibitors of activated (phosphorylated) JAK2, although markedly weaker than clinically tested ATP-competitive JAK2 inhibitors. Relatively small structural changes in the studied compounds affected interactions with JAK2, and their mode of action ranged from allosteric-noncompetitive to bisubstratecompetitive. These results demonstrated that direct inhibition of JAK2 enzymatic activity by the WP1065 (half-maximal inhibitory concentration [IC₅₀] = 14.8 µM), WP1130 (IC₅₀ = 3.8 µM), and WP1702 (IC₅₀ = 2.9 µM) potentially contributes, albeit minimally, to suppression of the JAK2/STAT signaling pathways in cancer cells and that additional specific structural modifications may amplify JAK2-inhibitory effects.
journal_name
Curr Cancer Drug Targetsjournal_title
Current cancer drug targetsauthors
Mielecki M,Milner-Krawczyk M,Grzelak K,Mielecki D,Krzysko KA,Lesyng B,Priebe Wdoi
10.2174/1568009614666140821122718subject
Has Abstractpub_date
2014-01-01 00:00:00pages
638-51issue
7eissn
1568-0096issn
1873-5576pii
CCDT-EPUB-61870journal_volume
14pub_type
杂志文章abstract:BACKGROUND:The solute carrier family 7 (SLC7) can be categorically divided into two subfamilies, the L-type amino acid transporters (LATs) including SLC7A5-13, and SLC7A15, and the cationic amino acid transporters (CATs) including SLC7A1-4 and SLC7A14. Members of the CAT family transport predominantly cationic amino ac...
journal_title:Current cancer drug targets
pub_type: 杂志文章,评审
doi:10.2174/1568009619666190802135714
更新日期:2019-01-01 00:00:00
abstract::The treatment of advanced non � small cell lung cancer (NSCLC) increasingly involves the use of molecularly targeted therapy with activity against either the tumor directly, or indirectly, through activity against host-derived mechanisms of tumor support such as angiogenesis. The most well studied signaling pathway as...
journal_title:Current cancer drug targets
pub_type: 杂志文章,评审
doi:10.2174/156800912799095144
更新日期:2012-02-01 00:00:00
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journal_title:Current cancer drug targets
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doi:10.2174/1568009615666150616123548
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abstract:BACKGROUND:Approximately one third of Diffuse Large B cell Lymphomas (DLBCL) are refractory or relapse. Novel therapeutic approaches under scrutiny include inhibitors of B-cell receptor (BCR) signaling. Protein kinase CK2 propels survival, proliferation and stress response in solid and hematologic malignancies and prom...
journal_title:Current cancer drug targets
pub_type: 杂志文章
doi:10.2174/1568009617666170427110450
更新日期:2018-01-01 00:00:00
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journal_title:Current cancer drug targets
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doi:10.2174/1568009615666150407125020
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abstract::Targets for cancer therapy are conventionally selected by identification of molecules acting downstream of established tumour suppressors and oncoproteins, such as p53, c-Myc and Ras. However, the forward genetics approach provides an alternative, conceptually distinct, strategy for identifying target molecules de nov...
journal_title:Current cancer drug targets
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更新日期:2013-01-01 00:00:00
abstract::Breast cancer is one of the most prevalent and devastating malignant diseases in women worldwide. Fortunately, while breast cancer incidence is still increasing, its death rate is declining. This is mainly due to early diagnosis and potent therapies such as blockade of estrogen receptor- or of ErbB2 (HER2-neu) membran...
journal_title:Current cancer drug targets
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journal_title:Current cancer drug targets
pub_type: 杂志文章
doi:10.2174/1568009620666201230090531
更新日期:2020-12-29 00:00:00
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journal_title:Current cancer drug targets
pub_type: 杂志文章,评审
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更新日期:2006-12-01 00:00:00
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journal_title:Current cancer drug targets
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更新日期:2012-11-01 00:00:00
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journal_title:Current cancer drug targets
pub_type: 杂志文章,评审
doi:10.2174/15680096113136660109
更新日期:2014-01-01 00:00:00
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journal_title:Current cancer drug targets
pub_type: 杂志文章
doi:10.2174/156800910793605839
更新日期:2010-11-01 00:00:00
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journal_title:Current cancer drug targets
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abstract::NUPR1 is a transcription factor that has attracted great attention because of its various roles in cancer. Several studies were carried out to determine its molecular targets and mechanism of action to develop novel therapies against cancer. Here, we shed light on the role of NUPR1 in different types of cancer. NUPR1 ...
journal_title:Current cancer drug targets
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doi:10.2174/1568009620666200703152523
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journal_title:Current cancer drug targets
pub_type: 杂志文章,评审
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更新日期:2003-02-01 00:00:00
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journal_title:Current cancer drug targets
pub_type: 杂志文章
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更新日期:2011-06-01 00:00:00
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journal_title:Current cancer drug targets
pub_type: 杂志文章
doi:10.2174/15680096113139990038
更新日期:2013-07-01 00:00:00
abstract::The histone deacetylase inhibitors are a new class of cytostatic agents that inhibit the proliferation of tumor cells in culture and in vivo by inducing cell cycle arrest, differentiation and/or apoptosis. Histone acetylation and deacetylation play important roles in the modulation of chromatin topology and the regula...
journal_title:Current cancer drug targets
pub_type: 杂志文章,评审
doi:10.2174/1568009043481560
更新日期:2004-03-01 00:00:00
abstract::FOXO proteins are evolutionarily conserved transcription factors implicated in several fundamental cellular processes, functioning as end-point for transcriptional programs involved in apoptosis, stress response and longevity. Abrogation of FOXO function is very frequent in human cancer, therefore the mechanisms of re...
journal_title:Current cancer drug targets
pub_type: 杂志文章
doi:10.2174/156800910791054158
更新日期:2010-03-01 00:00:00
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journal_title:Current cancer drug targets
pub_type: 杂志文章
doi:10.2174/1568009620666200720010647
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journal_title:Current cancer drug targets
pub_type: 杂志文章
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journal_title:Current cancer drug targets
pub_type: 杂志文章
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abstract::Cisplatin is one of the most commonly used drugs in the treatment of gastric cancer. However, drug resistance is a major obstacle for effective treatment and originates in multiple mechanisms such as enhanced DNA repair and anti-apoptosis. Our previous results demonstrated that XRCC1 was a key regulator of cisplatin i...
journal_title:Current cancer drug targets
pub_type: 杂志文章
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更新日期:2015-01-01 00:00:00
abstract::Glioma-associated oncogenes (GLIs) are zinc finger protein family members and downstream regulatory factors of the classic Hedgehog (Hh) signaling pathway. GLI proteins influence the growth and development of organisms and aid in tissue repair. However, aberrant expression of the GLI family member GLI1 promotes carcin...
journal_title:Current cancer drug targets
pub_type: 杂志文章,评审
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更新日期:2018-01-01 00:00:00
abstract::The evolution of genomic research enabled the genetic and molecular profiling of breast cancer and revealed the profound complexity and heterogeneity of this disease. Subtypes of breast cancer characterized by mutations and/or amplifications of some proto-oncogenes are associated with an increased rate of recurrence a...
journal_title:Current cancer drug targets
pub_type: 杂志文章,评审
doi:10.2174/1568009616666160603123014
更新日期:2017-01-01 00:00:00
abstract::Amplification of the HER-2 gene occurs in approximately 25% of breast cancers, causing up-regulation of key signaling pathways which control cell growth and survival. In breast cancer patients, HER-2 overexpression correlates with an aggressive phenotype and poor prognosis. HER-2, therefore, has become the focus of ma...
journal_title:Current cancer drug targets
pub_type: 杂志文章,评审
doi:10.2174/156800909788166484
更新日期:2009-05-01 00:00:00
abstract::Angiotensin II (Ang II), a main effector peptide of the renin-angiotensin system (RAS), mediates a hormonal action in the maintenance of blood pressure and electrolyte levels, and thus fluid homeostasis. Ang II also mediates paracrine, autocrine and/or intracrine actions in the control of various specific functions of...
journal_title:Current cancer drug targets
pub_type: 杂志文章,评审
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更新日期:2011-05-01 00:00:00
abstract::Heat shock protein 32 (Hsp32), also known as heme oxygenase-1 (HO-1), is a stress-related anti-apoptotic molecule, that has been implicated in enhanced survival of neoplastic cells and in drug-resistance. We here show that Hsp32 is expressed in most solid tumors and hematopoietic neoplasms and may be employed as a new...
journal_title:Current cancer drug targets
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更新日期:2009-08-01 00:00:00
abstract:BACKGROUND:MicroRNA (miRNA) therapy, which was widely considered to treat a series of cancer, has been confronted with numerous obstacles to being delivered into target cells because of its easy biodegradation and instability. METHODS:In this research, we successfully constructed 11-mercaptoundecanoic acid modified go...
journal_title:Current cancer drug targets
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更新日期:2019-01-01 00:00:00
abstract:BACKGROUND:CYP1B1 is recognized as a valuable target for chemotherapy. It catalyzes the bioactivation of naphthoquinone oximes within certain cancer cell lines. However, the expression level of CYP1B1 in melanoma and the functional role regulating the activity of DMAKO-20 as a representative naphthoquinone oxime agains...
journal_title:Current cancer drug targets
pub_type: 杂志文章
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更新日期:2020-11-15 00:00:00