A small-molecule inhibitor of Haspin alters the kinetochore functions of Aurora B

By phosphorylating Thr3 of histone H3, Haspin promotes centromeric recruitment of the chromosome passenger complex (CPC) during mitosis. Aurora B kinase, a CPC subunit, sustains chromosome bi-orientation and the spindle assembly checkpoint (SAC). Here, we characterize the small molecule 5-iodotubercidin (5-ITu) as a potent Haspin inhibitor. In vitro, 5-ITu potently inhibited Haspin but not Aurora B. Consistently, 5-ITu counteracted the centromeric localization of the CPC without affecting the bulk of Aurora B activity in HeLa cells. Mislocalization of Aurora B correlated with dephosphorylation of CENP-A and Hec1 and SAC override at high nocodazole concentrations. 5-ITu also impaired kinetochore recruitment of Bub1 and BubR1 kinases, and this effect was reversed by concomitant inhibition of phosphatase activity. Forcing localization of Aurora B to centromeres in 5-ITu also restored Bub1 and BubR1 localization but failed to rescue the SAC override. This result suggests that a target of 5-ITu, possibly Haspin itself, may further contribute to SAC signaling downstream of Aurora B.

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Small molecule inhibitor of nicotinamide N-methyltransferase shows anti-proliferative activity in HeLa cells

Journal of Obstetrics and Gynaecology ◽

10.1080/01443615.2020.1854696 ◽

2021 ◽

pp. 1-9

Author(s):

Serra Akar ◽

Tuğçe Duran ◽

Ali Ahmed Azzawri ◽

Nadir Koçak ◽

Çetin Çelik ◽

...

Keyword(s):

Small Molecule ◽

Hela Cells ◽

Proliferative Activity ◽

Small Molecule Inhibitor ◽

Molecule Inhibitor

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A Novel Small-Molecule Inhibitor of Protein Kinase D Blocks Pancreatic Cancer Growth In vitro and In vivo

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-09-1145 ◽

2010 ◽

Vol 9 (5) ◽

pp. 1136-1146 ◽

Cited By ~ 95

Author(s):

Kuzhuvelil B. Harikumar ◽

Ajaikumar B. Kunnumakkara ◽

Nobuo Ochi ◽

Zhimin Tong ◽

Amit Deorukhkar ◽

...

Keyword(s):

Pancreatic Cancer ◽

Protein Kinase ◽

Small Molecule ◽

Small Molecule Inhibitor ◽

Cancer Growth ◽

Protein Kinase D ◽

Molecule Inhibitor

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Patient-Derived Three-Dimensional Cortical Neurospheres to Model Parkinson′s Disease

10.1101/2021.08.21.457201 ◽

2021 ◽

Author(s):

Waseem K. Raja ◽

Esther Neves ◽

Christopher Burke ◽

Xin Jiang ◽

Ping Xu ◽

...

Keyword(s):

Fatty Acid ◽

Small Molecule ◽

Three Dimensional ◽

Underlying Disease ◽

Alpha Synuclein ◽

Protein Accumulation ◽

Molecule Inhibitor ◽

Induced Pluripotent ◽

Small Molecule Therapeutics

There are currently no preventive or disease-modifying therapies for Parkinson′s Disease (PD). Failures in clinical trials necessitate a re-evaluation of existing pre-clinical models in order to adopt systems that better recapitulate underlying disease mechanisms and better predict clinical outcomes. In recent years, models utilizing patient-derived induced pluripotent stem cells (iPSCs) have emerged as attractive models to recapitulate disease-relevant neuropathology in vitro without exogenous overexpression of disease-related pathologic proteins. Here, we utilized iPSCs derived from patients with early-onset PD and dementia phenotypes that harbored either a point mutation (A53T) or multiplication at the Alpha-synuclein/SNCA gene locus. We generated a three-dimensional (3D) cortical neurosphere culture model to better mimic the tissue microenvironment of the brain. We extensively characterized the differentiation process using quantitative PCR, Western immunoblotting, and immunofluorescence staining. Differentiation and aging of the neurospheres revealed alterations in fatty acid profiles and elevated total and pathogenic phospho-Alpha-synuclein levels in both A53T and the triplication lines compared to their isogenic control lines. Furthermore, treatment of the neurospheres with a small molecule inhibitor of stearoyl CoA desaturase (SCD) attenuated the protein accumulation and aberrant fatty acid profile phenotypes. Our findings suggest that the 3D cortical neurosphere model is a useful tool to interrogate targets for PD and amenable to test small molecule therapeutics.

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Use of the Novel Plk1 Inhibitor ZK-Thiazolidinone to Elucidate Functions of Plk1 in Early and Late Stages of Mitosis

Molecular Biology of the Cell ◽

10.1091/mbc.e07-05-0517 ◽

2007 ◽

Vol 18 (10) ◽

pp. 4024-4036 ◽

Cited By ~ 132

Author(s):

Anna Santamaria ◽

Rüdiger Neef ◽

Uwe Eberspächer ◽

Knut Eis ◽

Manfred Husemann ◽

...

Keyword(s):

Spindle Assembly Checkpoint ◽

Spindle Assembly ◽

Cleavage Furrow ◽

The Novel ◽

Mitotic Progression ◽

Binding Partner ◽

Molecule Inhibitor ◽

Interaction Partners ◽

Late Stages

Polo-like kinase 1 (Plk1) is a key regulator of mitotic progression and cell division in eukaryotes. It is highly expressed in tumor cells and considered a potential target for cancer therapy. Here, we report the discovery and application of a novel potent small-molecule inhibitor of mammalian Plk1, ZK-Thiazolidinone (TAL). We have extensively characterized TAL in vitro and addressed TAL specificity within cells by studying Plk1 functions in sister chromatid separation, centrosome maturation, and spindle assembly. Moreover, we have used TAL for a detailed analysis of Plk1 in relation to PICH and PRC1, two prominent interaction partners implicated in spindle assembly checkpoint function and cytokinesis, respectively. Specifically, we show that Plk1, when inactivated by TAL, spreads over the arms of chromosomes, resembling the localization of its binding partner PICH, and that both proteins are mutually dependent on each other for correct localization. Finally, we show that Plk1 activity is essential for cleavage furrow formation and ingression, leading to successful cytokinesis.

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Centromere-localized Aurora B kinase is required for the fidelity of chromosome segregation

The Journal of Cell Biology ◽

10.1083/jcb.201907092 ◽

2019 ◽

Vol 219 (2) ◽

Cited By ~ 9

Author(s):

Cai Liang ◽

Zhenlei Zhang ◽

Qinfu Chen ◽

Haiyan Yan ◽

Miao Zhang ◽

...

Keyword(s):

Chromosome Segregation ◽

Essential Role ◽

Spindle Assembly Checkpoint ◽

Histone H3 ◽

Spindle Assembly ◽

Aurora B ◽

Aurora B Kinase ◽

Chromosome Missegregation ◽

Proper Timing ◽

Segregation Of Chromosomes

Aurora B kinase plays an essential role in chromosome bi-orientation, which is a prerequisite for equal segregation of chromosomes during mitosis. However, it remains largely unclear whether centromere-localized Aurora B is required for faithful chromosome segregation. Here we show that histone H3 Thr-3 phosphorylation (H3pT3) and H2A Thr-120 phosphorylation (H2ApT120) can independently recruit Aurora B. Disrupting H3pT3-mediated localization of Aurora B at the inner centromere impedes the decline in H2ApT120 during metaphase and causes H2ApT120-dependent accumulation of Aurora B at the kinetochore-proximal centromere. Consequently, silencing of the spindle assembly checkpoint (SAC) is delayed, whereas the fidelity of chromosome segregation is negligibly affected. Further eliminating an H2ApT120-dependent pool of Aurora B restores proper timing for SAC silencing but increases chromosome missegregation. Our data indicate that H2ApT120-mediated localization of Aurora B compensates for the loss of an H3pT3-dependent pool of Aurora B to correct improper kinetochore–microtubule attachments. This study provides important insights into how centromeric Aurora B regulates SAC and kinetochore attachment to microtubules to ensure error-free chromosome segregation.

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Thermostable small-molecule inhibitor of angiogenesis and vascular permeability that suppresses a pERK-FosB/ΔFosB–VCAM-1 axis

Science Advances ◽

10.1126/sciadv.aaz7815 ◽

2020 ◽

Vol 6 (31) ◽

pp. eaaz7815

Author(s):

Yue Li ◽

Ahmad M. N. Alhendi ◽

Mei-Chun Yeh ◽

Mina Elahy ◽

Fernando S. Santiago ◽

...

Keyword(s):

Vascular Permeability ◽

Small Molecule ◽

Wound Repair ◽

Network Formation ◽

Small Molecule Inhibitor ◽

Age Related Macular Degeneration ◽

Endothelial Cell Proliferation ◽

Age Related ◽

Molecule Inhibitor

Vascular permeability and angiogenesis underpin neovascular age-related macular degeneration and diabetic retinopathy. While anti-VEGF therapies are widely used clinically, many patients do not respond optimally, or at all, and small-molecule therapies are lacking. Here, we identified a dibenzoxazepinone BT2 that inhibits endothelial cell proliferation, migration, wound repair in vitro, network formation, and angiogenesis in mice bearing Matrigel plugs. BT2 interacts with MEK1 and inhibits ERK phosphorylation and the expression of FosB/ΔFosB, VCAM-1, and many genes involved in proliferation, migration, angiogenesis, and inflammation. BT2 reduced retinal vascular leakage following rat choroidal laser trauma and rabbit intravitreal VEGF-A165 administration. BT2 suppressed retinal CD31, pERK, VCAM-1, and VEGF-A165 expression. BT2 reduced retinal leakage in rats at least as effectively as aflibercept, a first-line therapy for nAMD/DR. BT2 withstands boiling or autoclaving and several months’ storage at 22°C. BT2 is a new small-molecule inhibitor of vascular permeability and angiogenesis.

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