SBE13, a newly identified inhibitor of inactive polo-like kinase 1

Poster presentation at 5th German Conference on Cheminformatics: 23. CIC-Workshop Goslar, Germany. 8-10 November 2009 Protein kinases are important targets for drug development. The almost identical protein folding of kinases and the common co-substrate ATP leads to the problem of inhibitor selectivity. Type II inhibitors, targeting the inactive conformation of kinases, occupy a hydrophobic pocket with less conserved surrounding amino acids. Human polo-like kinase 1 (Plk1) represents a promising target for approaches to identify new therapeutic agents. Plk1 belongs to a family of highly conserved serine/threonine kinases, and is a key player in mitosis, where it modulates the spindle checkpoint at metaphase/anaphase transition. Plk1 is over-expressed in all today analyzed human tumors of different origin and serves as a negative prognostic marker in cancer patients. The newly identified inhibitor, SBE13, a vanillin derivative, targets Plk1 in its inactive conformation. This leads to selectivity within the Plk family and towards Aurora A. This selectivity can be explained by docking studies of SBE13 into the binding pocket of homology models of Plk1, Plk2 and Plk3 in their inactive conformation. SBE13 showed anti-proliferative effects in cancer cell lines of different origins with EC50 values between 5 microM and 39 microM and induced apoptosis. Increasing concentrations of SBE13 result in increasing amounts of cells in G2/M phase 13 hours after double thymidin block of HeLa cells. The kinase activity of Plk1 was inhibited with an IC50 of 200 pM. Taken together, we could show that carefully designed structure-based virtual screening is well-suited to identify selective type II kinase inhibitors targeting Plk1 as potential anti-cancer therapeutics

Illustrated key to the genera of free-living marine nematodes of the Order Enoplida

A pictorial key to US genera of free-living marine nematodes in the order Enoplida is presented. Specific morphological and anatomical features are iUustrated to facilitate use of the key. The purpose of this work is to provide a single key to the genera of enoplid nematodes to facilitate identification of these organisms by nematologists and marine biologists working with meiofauna. (PDF file contains 32 pages.

A Redescription of Oncholaimoides elongatus Hopper, 1961 (Nematoda: Enoplida) with Descriptions of the Other Two Members of the Genus

Oncholaimoides elongatus is redescribed from specimens collected from subtidal, shallow-water sediments from the Gulf of Mexico, Bay County, Florida. The original description of this species was based on a single male specimen from the Gulf of Mexico, Baldwin County, Alabama. Descriptions of Oncholaimoides rugosus and Oncholaimoides striatus from subtidal sediments of St. Andrew Bay, Bay County, Florida are given. A key to the species of Oncholaimoides is provided

A New Species and Two Known Species of Free-Living Marine Nematodes (Nematoda: Monoposthiidae) from Northwest Florida, U.S.A.

Two known free-living marine nematodes, Monoposthioides mayri Wieser and Hopper, 1967 and Monoposthia hexalata Chitwood. 1936 are redescribed from sediments in St. Andrew Bay and Lake Powell, Bay County, Florida, U.S.A. One new species of free-living marine nematode, Monoposthia baxteri n. sp., is described from nonvegetated sediments in St. Andrew Bay, Bay County, Florida. M. baxteri n. sp. differs from the other members of the genus in the shape of the gubernaculum which is more similar to that of the species of Monoposthioides than that of Monoposthia

Eleven New Species of Free-Living Marine Nematodes

The genus Halalaimus is reviewed and divided into four groups based on characters of the male. Characters used to separate the groups of males include presence or absence of caudal algae and the presence or absence of a precloacal sensillum and/or pore. Ten new species are described from St. Andrew Bay, Bay County, Florida, and H. gerlachi n. sp. is proposed for H. gracilis sensu GerIach, 1967. New species from St. Andrew Bay are H. thalassinus, H. tarjani, H. bayensis, H. bulbocaudatus, H. variabilis, H. paracomatus, H. americanus, H. floridanus, H. brimi, and H. parafletcheri. Keys to the species of each group are provided based on characters of the male. A key to the females of the genus is also provided

Identification of Plk1 type II inhibitors by structure-based virtual screening

Protein kinases are targets for drug development. Dysregulation of kinase activity leads to various diseases, e.g. cancer, inflammation, diabetes. Human polo-like kinase 1 (Plk1), a serine/threonine kinase, is a cancer-relevant gene and a potential drug target which attracts increasing attention in the field of cancer therapy. Plk1 is a key player in mitosis and modulates entry into mitosis and the spindle checkpoint at the meta-/anaphase transition. Plk1 overexpression is observed in various human tumors, and it is a negative prognostic factor for cancer patients. The same catalytical mechanism and the same co-substrate (ATP) lead to the problem of inhibitor selectivity. A strategy to solve this problem is represented by targeting the inactive conformation of kinases. Kinases undergo conformational changes between active and inactive conformation and thus an additional hydrophobic pocket is created in the inactive conformation where the surrounding amino acids are less conserved. A "homology model" of the inactive conformation of Plk1 was constructed, as the crystal structure in its inactive conformation is unknown. A crystal structure of Aurora A kinase served as template structure. With this homology model a receptor-based pharmacophore search was performed using SYBYL7.3 software. The raw hits were filtered using physico-chemical properties. The resulting hits were docked using Gold3.2 software, and 13 candidates for biological testing were manually selected. Three compounds of the 13 tested exhibit anti-proliferative effects in HeLa cancer cells. The most potent inhibitor, SBE13, was further tested in various other cancer cell lines of different origins and displayed EC50 values between 12 microM and 39 microM. Cancer cells incubated with SBE13 showed induction of apoptosis, detected by PARP (Poly-Adenosyl-Ribose-Polymerase) cleavage, caspase 9 activation and DAPI staining of apoptotic nuclei

Eleven New Species of Free-Living Marine Nematodes

The genus Halalaimus is reviewed and divided into four groups based on characters of the male. Characters used to separate the groups of males include presence or absence of caudal algae and the presence or absence of a precloacal sensillum and/or pore. Ten new species are described from St. Andrew Bay, Bay County, Florida, and H. gerlachi n. sp. is proposed for H. gracilis sensu GerIach, 1967. New species from St. Andrew Bay are H. thalassinus, H. tarjani, H. bayensis, H. bulbocaudatus, H. variabilis, H. paracomatus, H. americanus, H. floridanus, H. brimi, and H. parafletcheri. Keys to the species of each group are provided based on characters of the male. A key to the females of the genus is also provided

Antibodies aggravate the development of ischemic heart failure

Heart-specific antibodies have been widely associated with myocardial infarction (MI). However, it remains unclear whether autoantibodies mediate disease progression or are a byproduct of cardiac injury. To disambiguate the role of immunoglobulins in MI, we characterized the development of ischemic heart failure in agammaglobulinemic mice (AID-/-μS-/-). Although these animals can produce functional B cells, they cannot synthesize secretory IgM (μS-/-) or perform Ig class switching (AID-/-), leading to complete antibody deficiency. Agammaglobulinemia did not affect overall post-MI survival but resulted in a significant reduction in infarct size. Echocardiographic analyses showed that, compared with wild-type infarcted control mice, AID-/-μS-/- mice exhibited improved cardiac function and reduced remodeling on day 56 post-MI. These differences remained significant even after animals with matched infarct sizes were compared. Infarcted AID-/-μS-/- mice also showed reduced myocardial expression levels of transcripts known to promote adverse remodeling, such as matrix metalloproteinase-9, collagen type I a1, collagen type III a1, and IL-6. An unbiased screening of the heart reactivity potential in the plasma of wild-type MI animals revealed the presence of antibodies that target the myocardial scar and collagenase-sensitive epitopes. Moreover, we found that IgG accumulated within the scar tissues of infarcted mice and remained in close proximity with cells expressing Fcγ receptors (CD16/32), suggesting the existence of an in situ IgG-Fcγ receptor axis. Collectively, our study results confirm that antibodies contribute to ischemic heart failure progression and provide novel insights into the mechanisms underlying this phenomenon. NEW & NOTEWORTHY Our study sheds some light on the long-standing debate over the relevance of autoantibodies in heart failure and might stimulate future research in the field. The observation of extracellular matrix-specific antibodies and the detection of Fcγ receptor-expressing cells within the scar provide novel insights into the mechanisms by which antibodies may contribute to adverse remodeling.info:eu-repo/semantics/publishedVersio