scholarly journals Crystal Structure of the Kinase Domain of MerTK in Complex with AZD7762 Provides Clues for Structure-Based Drug Development

2020 ◽  
Vol 21 (21) ◽  
pp. 7878
Author(s):  
Tae Hyun Park ◽  
Seung-Hyun Bae ◽  
Seoung Min Bong ◽  
Seong Eon Ryu ◽  
Hyonchol Jang ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Cancer Cell ◽  
Structural Information ◽  
Antiplatelet Agents ◽  
Binding Mode ◽  
Kinase Domain ◽  
Chemical Library ◽  
Time Resolved ◽  
Cancer Cell Death

Aberrant tyrosine-protein kinase Mer (MerTK) expression triggers prosurvival signaling and contributes to cell survival, invasive motility, and chemoresistance in many kinds of cancers. In addition, recent reports suggested that MerTK could be a primary target for abnormal platelet aggregation. Consequently, MerTK inhibitors may promote cancer cell death, sensitize cells to chemotherapy, and act as new antiplatelet agents. We screened an inhouse chemical library to discover novel small-molecule MerTK inhibitors, and identified AZD7762, which is known as a checkpoint-kinase (Chk) inhibitor. The inhibition of MerTK by AZD7762 was validated using an in vitro homogeneous time-resolved fluorescence (HTRF) assay and through monitoring the decrease in phosphorylated MerTK in two lung cancer cell lines. We also determined the crystal structure of the MerTK:AZD7762 complex and revealed the binding mode of AZD7762 to MerTK. Structural information from the MerTK:AZD7762 complex and its comparison with other MerTK:inhibitor structures gave us new insights for optimizing the development of inhibitors targeting MerTK.

scholarly journals Crystal Structure of Human α-2,6 Sialyltransferase

2014 ◽  
Vol 70 (a1) ◽  
pp. C307-C307
Author(s):  
Bernd Kuhn ◽  
Jörg Benz ◽  
Michael Greif ◽  
Alfred Engel ◽  
Harald Sobek ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Serine Proteases ◽  
Structural Information ◽  
Binding Mode ◽  
Glycosylation Pattern ◽  
Terminal Galactose ◽  
A Charge ◽  
Insight Into ◽  
St6gal I

Human β-galactoside α-2,6 sialyltransferase I (ST6Gal-I) establishes the final glycosylation pattern of many glycoproteins by transferring a sialyl moiety to a terminal galactose. Complete sialylation of therapeutic immunoglobulins is essential for their anti-inflammatory activity and for protein stability. However, a complete glycan tree is difficult to achieve in vitro due to limited activity of ST6Gal-I for some galactose acceptors. No structural information on ST6Gal-I that could help to improve the enzymatic properties of ST6Gal-I for biotechnological purposes was previously available. We describe the crystal structure of human ST6Gal-I, which allows rationalizing the inhibitory activity of cytosine-based nucleotides. ST6Gal-I differs from related sialyltransferases by several large insertions and deletions that determine its regio- and substrate specificity. Excitingly, a large glycan binds to the active site in a catalytically competent orientation, representing the general binding mode of any substrate glycoprotein. This binding mode also rationalizes why some galactose acceptors are incompletely sialylated. Comparison with a bacterial sialyltransferase lends first insight into the Michaelis complex. The results support an SN2 mechanism with inversion of configuration at the sialyl residue and suggest substrate-assisted catalysis with a charge relay mechanism that bears conceptual similarity to serine proteases.

An iron(iii) complex selectively mediated cancer cell death: crystal structure, DNA targeting and in vitro antitumor activities

2019 ◽  
Vol 6 (4) ◽  
pp. 1040-1049 ◽  
Author(s):  
Yi-Gang Wu ◽  
Dong-Bo Wang ◽  
Juan-Juan Hu ◽  
Xue-Qing Song ◽  
Cheng-Zhi Xie ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Cell Death ◽  
Cancer Cell ◽  
Selectivity Index ◽  
Antitumor Activities ◽  
Normal Cells ◽  
Dna Targeting ◽  
Cancer Cell Death

Three new iron(iii) complexes were prepared, and complex 3 exhibited a 14-fold higher selectivity index for HeLa vs. LO2 normal cells than cisplatin.

scholarly journals STK32A is a dual-specificity AGC kinase with a preference for acidic substrates

2020 ◽  
Author(s):  
Fiona J. Sorrell ◽  
Fabrizio Miranda ◽  
Kamal R. Abdul Azeez ◽  
Apirat Chaikuad ◽  
Arminja N. Kettenbach ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Kinase Inhibitors ◽  
Alpha Helix ◽  
Binding Mode ◽  
Kinase Domain ◽  
Peptide Sequence ◽  
Kinase Family ◽  
Dual Specificity ◽  
Hydrophobic Motif

AbstractThe STK32 kinases are a small subfamily of three uncharacterised serine/threonine kinases from the AGC kinase family whose functional role is so far unknown. Here, we analyse the consensus peptide sequence for STK32A phosphorylation, showing that STK32A is directed towards acidic substrate sequences and exhibits dual-specificity for serine/threonine and tyrosine residues. A crystal structure of STK32A reveals an overall structure typical of the AGC protein kinase family but with significant and unique features including an altered binding mode of the hydrophobic motif to the N-terminal lobe of the kinase domain, and a novel alpha-helix in between the turn motif and the hydrophobic motif. The crystal structure combined with phylogenetic analysis reveals the evolutionary conservation of the acidic substrate preference. In vitro binding assays demonstrated that the STK32 kinases bind significant numbers of clinically used kinase inhibitors.

scholarly journals Selenium Induces Pancreatic Cancer Cell Death Alone and in Combination with Gemcitabine

Biomedicines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 149
Author(s):  
David J. Wooten ◽  
Indu Sinha ◽  
Raghu Sinha
Keyword(s):  
Pancreatic Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Single Agent ◽  
Cancer Cell Lines ◽  
Chemotherapeutic Agents ◽  
Cancer Cell Death ◽  
Pancreatic Cancer Cells

Survival rate for pancreatic cancer remains poor and newer treatments are urgently required. Selenium, an essential trace element, offers protection against several cancer types and has not been explored much against pancreatic cancer specifically in combination with known chemotherapeutic agents. The present study was designed to investigate selenium and Gemcitabine at varying doses alone and in combination in established pancreatic cancer cell lines growing in 2D as well as 3D platforms. Comparison of multi-dimensional synergy of combinations’ (MuSyc) model and highest single agent (HSA) model provided quantitative insights into how much better the combination performed than either compound tested alone in a 2D versus 3D growth of pancreatic cancer cell lines. The outcomes of the study further showed promise in combining selenium and Gemcitabine when evaluated for apoptosis, proliferation, and ENT1 protein expression, specifically in BxPC-3 pancreatic cancer cells in vitro.

scholarly journals Targeting N-myristoylation for therapy of B-cell lymphomas

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Erwan Beauchamp ◽  
Megan C. Yap ◽  
Aishwarya Iyer ◽  
Maneka A. Perinpanayagam ◽  
Jay M. Gamma ◽  
...  
Keyword(s):  
B Cell ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Cell Receptor ◽  
B Cell Lymphomas ◽  
Cancer Cell Death ◽  
Anti Cancer ◽  
Xenograft Models ◽  
Patients Experience

Abstract Myristoylation, the N-terminal modification of proteins with the fatty acid myristate, is critical for membrane targeting and cell signaling. Because cancer cells often have increased N-myristoyltransferase (NMT) expression, NMTs were proposed as anti-cancer targets. To systematically investigate this, we performed robotic cancer cell line screens and discovered a marked sensitivity of hematological cancer cell lines, including B-cell lymphomas, to the potent pan-NMT inhibitor PCLX-001. PCLX-001 treatment impacts the global myristoylation of lymphoma cell proteins and inhibits early B-cell receptor (BCR) signaling events critical for survival. In addition to abrogating myristoylation of Src family kinases, PCLX-001 also promotes their degradation and, unexpectedly, that of numerous non-myristoylated BCR effectors including c-Myc, NFκB and P-ERK, leading to cancer cell death in vitro and in xenograft models. Because some treated lymphoma patients experience relapse and die, targeting B-cell lymphomas with a NMT inhibitor potentially provides an additional much needed treatment option for lymphoma.

Synthesis, Crystal Structure, DNA-binding Properties and Antioxidant Activities of a Lutetium(III) Complex with the Bis(N-salicylidene)-3- oxapentane-1,5-diamine Ligand

2013 ◽  
Vol 68 (3) ◽  
pp. 257-266 ◽  
Author(s):  
Guolong Pan ◽  
Yuchen Bai ◽  
Hua Wang ◽  
Jin Kong ◽  
Furong Shi ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Dna Binding ◽  
Antioxidant Activities ◽  
Radical Scavenging ◽  
Binding Mode ◽  
Binding Properties ◽  
Metal Centers ◽  
Spectrophotometric Methods ◽  
Dna Binding Properties

A Schiff base ligand bis(N-salicylidene)-3-oxapentane-1,5-diamine (H2L) and its lutetium(III) complex, with composition Lu2(L)2(NO3)2, were synthesized and characterized by physico-chemical and spectroscopic methods. The crystal structure of the Lu(III) complex has been determined by single-crystal X-ray diffraction. It reveals a centrosymmetric binuclear neutral entity where Lu(III) metal centers are bridged by two phenoxo oxygen atoms. The DNA-binding properties of the Lu(III) complex were investigated by spectrophotometric methods and viscosity measurements, and the results suggest that the Lu(III) complex binds to DNA via a groove binding mode. Additionally, the antioxidant activity of the Lu(III) complex was determined by the superoxide and hydroxyl radical scavenging methods in vitro, which indicate that it is a scavenger for OH· and O-· 2 radicals.

scholarly journals Involvement of general control nonderepressible kinase 2 in cancer cell apoptosis by posttranslational mechanisms

2015 ◽  
Vol 26 (6) ◽  
pp. 1044-1057 ◽  
Author(s):  
Chen Wei ◽  
Ma Lin ◽  
Bian Jinjun ◽  
Feng Su ◽  
Cao Dan ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cell ◽  
Protein Level ◽  
Cell Apoptosis ◽  
General Control ◽  
Screening Assay ◽  
Cancer Cell Apoptosis ◽  
Cancer Cell Death

General control nonderepressible kinase 2 (GCN2) is a promising target for cancer therapy. However, the role of GCN2 in cancer cell survival or death is elusive; further, small molecules targeting GCN2 signaling are not available. By using a GCN2 level-based drug screening assay, we found that GCN2 protein level critically determined the sensitivity of the cancer cells toward Na+,K+-ATPase ligand–induced apoptosis both in vitro and in vivo, and this effect was largely dependent on C/EBP homologous protein (CHOP) induction. Further analysis revealed that GCN2 is a short-lived protein. In A549 lung carcinoma cells, cellular β-arrestin1/2 associated with GCN2 and maintained the GCN2 protein level at a low level by recruiting the E3 ligase NEDD4L and facilitating consequent proteasomal degradation. However, Na+,K+-ATPase ligand treatment triggered the phosphorylation of GCN2 at threonine 899, which increased the GCN2 protein level by disrupting the formation of GCN2–β-arrestin–NEDD4L ternary complex. The enhanced GCN2 level, in turn, aggravated Na+,K+-ATPase ligand–induced cancer cell apoptosis. Our findings reveal that GCN2 can exert its proapoptotic function in cancer cell death by posttranslational mechanisms. Moreover, Na+,K+-ATPase ligands emerge as the first identified small-molecule drugs that can trigger cancer cell death by modulating GCN2 signaling.

pH-Triggered burst intracellular release from hollow microspheres to induce autophagic cancer cell death

2015 ◽  
Vol 3 (48) ◽  
pp. 9383-9396 ◽  
Author(s):  
Xin Liang ◽  
Ying Yang ◽  
Lijun Wang ◽  
Xianbing Zhu ◽  
Xiaowei Zeng ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cell ◽  
Hollow Microspheres ◽  
Cancer Cell Death ◽  
Intracellular Release

Rapamycin–NaHCO3-loaded HMs combined CQ–NaHCO3-loaded HMs could efficiently induce cancer cell death through apoptosis with autophagosome both in vitro and in vivo.

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