In vitro and in vivo characterization of a benzofuran derivative, a potential anticancer agent, as a novel Aurora B kinase inhibitor.

Aurora B is a serine/threonine kinase that has a key role in mitosis and is overexpressed in cancer cells. Aberrations in Aurora B are highly correlated with tumorigenesis and cancer development, so many studies have focused on the development of Aurora B kinase inhibitors. Based on one of our previous high-throughput screening studies, we identified lead compound S6, a small-molecule benzofuran derivative that binds Aurora B and inhibits its kinase activity in vitro.

Optimized protein kinase Cθ (PKCθ) inhibitors reveal only modest anti-inflammatory efficacy in a rodent model of arthritis.

We previously demonstrated that selective inhibition of protein kinase Cθ (PKCθ) with triazinone 1 resulted in dose-dependent reduction of paw swelling in a mouse model of arthritis.1,2 However, a high concentration was required for efficacy, thus providing only a minimal safety window. Herein we describe a strategy to deliver safer compounds based on the hypothesis that optimization of potency in concert with good oral pharmacokinetic (PK) properties would enable in vivo efficacy at reduced exposures, resulting in an improved safety window.

Discovery of selective and orally bioavailable protein kinase Cθ (PKCθ) inhibitors from a fragment hit.

Protein kinase Cθ (PKCθ) regulates a key step in the activation of T cells. On the basis of its mechanism of action, inhibition of this kinase is hypothesized to serve as an effective therapy for autoimmune diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis. Herein, the discovery of a small molecule PKCθ inhibitor is described, starting from a fragment hit 1 and advancing to compound 41 through the use of structure-based drug design.

A thienopyrimidine derivative induces growth inhibition and apoptosis in human cancer cell lines via inhibiting Aurora B kinase activity.

Aurora kinases play a key role in the regulation of mitosis and have been regarded as promising targets of cancer therapy. In this paper we describe a thienopyrimidine derivative (S7), a novel potent ATP-competitive hit inhibitor of Aurora B kinase screened through a HTS system, with the IC50 141.12 nM in the biochemical kinase activity assay.

S39, a novel Aurora B kinase inhibitor, shows potent antineoplastic activity in human Hela cervical cancer cell line.

Aurora kinases, frequently detected to be over-expressing in human tumors, regulate many essential events during mitosis progression and have been regarded as potentially important targets for cancer therapy. S39 is a novel potent inhibitor of Aurora B kinase with the IC50 90.07 nM in the biochemical assay in an ATP competitive manner.

The dietary flavonoid luteolin inhibits Aurora B kinase activity and blocks proliferation of cancer cells.

In human, Aurora B is a chromosomal passenger protein that induces phosphorylation of histone and involves in spindle checkpoint and cytokinesis. Aberrant expression of Aurora B has been shown to correlate with genetic instability and carcinogenesis. In the past, Aurora B has been validated as a drug target by several studies.

Identification and characterization of human LYPD6, a new member of the Ly-6 superfamily.

The Ly-6 protein superfamily is usually identified as a group of proteins with a LU protein domain. LU domain is about 80 amino acids long and characterized by a conserved pattern of 10 cysteine residues. Here we report the cloning and characterization of a novel human LU domain containing gene, LYPD6, isolated from human testis cDNA library, and mapped to 2q23.

3-Hydroxyflavone inhibits endogenous Aurora B and induces growth inhibition of cancer cell line.

The Aurora kinases play a critical role in mitosis and have been suggested as promising targets for cancer therapy due to their frequent overexpression in a variety of tumors. Compared with established inhibitors of cell division such as the anti-tubulins, novel agents target mitotic enzymes and show similar efficacy but with fewer side effects. Several small-molecule inhibitors of Aurora kinases have been developed as anticancer agents, some of which have progressed to early clinical evaluation.

Cloning and characterization of a human LYPD7, a new member of the Ly-6 superfamily.

Members of the Ly-6 (Lymphocyte Antigen 6) protein family share one or several repeat units of the LU domain that is defined by a distinct disulfide bonding pattern between 8 or 10 cysteine residues. Here we report the cloning and characterization of a novel human LU domain-containing gene, LYPD7 (LY6/PLAUR domain containing 7), isolated from human testis cDNA library, and mapped to 2q22.3-23.

Identification of a novel human zinc finger gene, ZNF438, with transcription inhibition activity.

There were many different families of zinc finger proteins that contained multiple cysteine and/or histidine residues and used zinc to stabilize their folds. The classical C2H2 zinc finger proteins were the founding members of this superfamily and were among the most abundant proteins in eukaryotic genomes. C2H2 proteins typically contained several C2H2 fingers that made tandem contacts along the DNA.

Cloning and characterization of a human GDPD domain-containing protein GDPD5.

Glycerophosphodiester phosphodiesterase (GDPD) catalyzes the hydrolysis of deacylated glycerophospholipids to glycerol phosphate and alcohol. GDPD5 has been reported in Mus musculus and Gallus gallus, but not in Homo sapiens. Here we report the cloning and characterization of a novel human GDPD domain-containing gene, GDPD5, isolated from human testis cDNA library, and mapped to 11q13.

Septin1, a new interaction partner for human serine/threonine kinase aurora-B.

Several families of kinases work together to ensure the rate and precision of mitosis. Aurora-B is an important serine/threonine kinase required for chromosome segregation and cytokinesis. Identification of Aurora-B substrates will help to enhance our understanding of the molecular mechanism of mitosis.