54 Biological characterization of ETP-45299, a selective small molecule inhibitor of PIM1, in human tumor cell lines

The palladium(II) bis-chelate complexes of the type [Pd(TSC1-5)2] (6–10), with their corresponding ligands 4-phenyl-1-(acetone)-thiosemicarbazone, HTSC1(1), 4-phenyl-1-(2′-chloro-benzaldehyde)-thiosemicarbazone, HTSC2(2), 4-phenyl-1-(3′-hydroxy-benzaldehyde)-thiosemicarbazone, HTSC3(3), 4-phenyl-1-(2′-naphthaldehyde)-thiosemicarbazone, HTSC4(4), and 4-phenyl-1-(1′-nitro-2′-naphthaldehyde)-thiosemicarbazone, HTSC5(5), were synthesized and characterized by elemental analysis and spectroscopic techniques (IR and1H- and13C-NMR). The molecular structure of HTSC3, HTSC4, and [Pd(TSC1)2] (6) have been determined by single crystal X-ray crystallography. Complex6shows a square planar geometry with two deprotonated ligands coordinated toPdIIthrough the azomethine nitrogen and thione sulfur atoms in acisarrangement. Thein vitrocytotoxic activity measurements indicate that the palladium(II) complexes (IC50=0.01–9.87 μM) exhibited higher antiproliferative activity than their free ligands (IC50=23.48–70.86 and >250 μM) against different types of human tumor cell lines. Among all the studied palladium(II) complexes, the [Pd(TSC3)2] (8) complex exhibited high antitumor activity on the DU145 prostate carcinoma and K562 chronic myelogenous leukemia cells, with low values of the inhibitory concentration (0.01 and 0.02 μM, resp.).Corrigendum to “Synthesis and Characterization of New Palladium(II) Thiosemicarbazone Complexes and Their Cytotoxic Activity against Various Human Tumor Cell Lines”

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The synthesis and characterization of a series of cobalt(II) β-ketoaminato complexes and their cytotoxic activity towards human tumor cell lines

Journal of Inorganic Biochemistry ◽

10.1016/j.jinorgbio.2011.03.005 ◽

2011 ◽

Vol 105 (6) ◽

pp. 858-866 ◽

Cited By ~ 10

Author(s):

Lydia Gurley ◽

Natalia Beloukhina ◽

Kalun Boudreau ◽

Andis Klegeris ◽

W. Stephen McNeil

Keyword(s):

Tumor Cell ◽

Cytotoxic Activity ◽

Cell Lines ◽

Human Tumor ◽

Synthesis And Characterization ◽

Tumor Cell Lines ◽

Human Tumor Cell ◽

Human Tumor Cell Lines

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Pharmacological disruption of the Notch transcription factor complex

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1922606117 ◽

2020 ◽

Vol 117 (28) ◽

pp. 16292-16301 ◽

Cited By ~ 3

Author(s):

Rajwinder Lehal ◽

Jelena Zaric ◽

Michele Vigolo ◽

Charlotte Urech ◽

Viktoras Frismantas ◽

...

Keyword(s):

Tumor Cell ◽

Notch Signaling ◽

Cell Lines ◽

Small Molecule ◽

Human Tumor ◽

Transcription Activation ◽

Receptor Activation ◽

Tumor Cell Lines ◽

Human Tumor Cell ◽

Human Tumor Cell Lines

Notch pathway signaling is implicated in several human cancers. Aberrant activation and mutations of Notch signaling components are linked to tumor initiation, maintenance, and resistance to cancer therapy. Several strategies, such as monoclonal antibodies against Notch ligands and receptors, as well as small-molecule γ-secretase inhibitors (GSIs), have been developed to interfere with Notch receptor activation at proximal points in the pathway. However, the use of drug-like small molecules to target the downstream mediators of Notch signaling, the Notch transcription activation complex, remains largely unexplored. Here, we report the discovery of an orally active small-molecule inhibitor (termed CB-103) of the Notch transcription activation complex. We show that CB-103 inhibits Notch signaling in primary human T cell acute lymphoblastic leukemia and other Notch-dependent human tumor cell lines, and concomitantly induces cell cycle arrest and apoptosis, thereby impairing proliferation, including in GSI-resistant human tumor cell lines with chromosomal translocations and rearrangements in Notch genes. CB-103 produces Notch loss-of-function phenotypes in flies and mice and inhibits the growth of human breast cancer and leukemia xenografts, notably without causing the dose-limiting intestinal toxicity associated with other Notch inhibitors. Thus, we describe a pharmacological strategy that interferes with Notch signaling by disrupting the Notch transcription complex and shows therapeutic potential for treating Notch-driven cancers.

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