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Luxeptinib (CG-806) simultaneously targets FLT3 and select other kinase pathways operative in myeloid malignancies. We investigated the range of kinases it inhibits, its cytotoxicity landscape ex vivo with acute myeloid leukemia (AML) patient samples, and its efficacy in xenograft models. Luxeptinib inhibits wild-type (WT) and many of the clinically relevant mutant forms of FLT3 at low nanomolar concentrations. It is a more potent inhibitor of the activity of FLT3-internal tandem duplication, FLT3 kinase domain and gatekeeper mutants than against WT FLT3. Broad kinase screens disclosed that it also inhibits other kinases that can drive oncogenic signaling and rescue pathways, but spares kinases known to be associated with clinical toxicity. In vitro profiling of luxeptinib against 186 AML fresh patient samples demonstrated greater potency relative to other FLT3 inhibitors, including cases with mutations in FLT3, isocitrate dehydrogenase-1/2, ASXL1, NPM1, SRSF2, TP53, or RAS, and activity was documented in a xenograft AML model. Luxeptinib administered continuously orally every 12 hours at a dose that yielded a mean Cmin plasma concentration of 1.0 ± 0.3 μmol/L (SEM) demonstrated strong antitumor activity but no myelosuppression or evidence of tissue damage in mice or dogs in acute toxicology studies. On the basis of these studies, luxeptinib was advanced into a phase I trial for patients with AML and myelodysplastic/myeloproliferative neoplasms.

Macrophages can harbor HIV for weeks while infecting nearby t cells, allowing the virus to elude treatment. adam Bennett et al. used a new imaging technique to examine how this [...]

Two newly discovered inhibitors kill Mycobacterium tuberculosis by selectively blocking its proteasome with high specificity (Nature 461, 621-626). Tuberculosis is difficult to treat in part because M. tuberculosis can enter [...]

To protect the body from harmful autoimmune reactions, T cells that react to self antigens are normally taken out of commission during their development in the thymus. However, some self-reactive [...]

Author(s): Pierrette Lo [1] A new national public health center might be in Canada's future, says Federal Health Minister Anne McLellan. The center, which would be similar to the US [...]

Author(s): Charlotte Schubert; Pierrette Lo Reining in EGF By combining a cell-based vaccine with monoclonal antibodies, cancer researchers have blasted tumors overexpressing the HER-2/neu receptor in mice. The mice are [...]

Author(s): Pierrette Lo Dendritic cells take up invading pathogens and other antigens, process them and present them to T cells. In the 1 May issue of Sciencexpress, David McDonald et [...]

Author(s): Pierrette Lo [1] Smallpox vaccinations began at the end of January in 17 states, amid lingering health and financial concerns. As Nature Medicine went to press, the Centers for [...]

The article presents abstracts on medical topics which include the discovery of PG9 and PG16 antibodies, the role of Blimp-1 in controlling T cell differentiation during viral infections, and the use of Insulin-like growth factor-1 (IGF-1) for the treatment of spinal bulbar muscular atrophy (SBMA).

The article presents news updates from the field of natural medicine. Faced with a growing AIDS epidemic in Eastern Europe and Central Asia, 55 European and Central Asian countries in February 2004 signed a declaration that would provide universal access to antiretroviral drugs by 2010. The Great Britain Medical Research Council in February 2004 announced a major funding overhaul. The agency plans to phase out its Cooperative Group Grants, which many had accused of forcing scientists into collaborations, with more diverse grants of varying sizes and durations, including a New Investigator Award for young scientists.

The article presents information related to some important researches. After a meal, pancreatic secretion of insulin tells peripheral tissues, mainly skeletal muscle and fat, to take up glucose. In type 2 diabetes, this signal is impaired by "resistance" of peripheral tissues to insulin. In 1995, researchers were quietly introduced to a molecule, now known as adiponectin, that would later emerge as a promising link between obesity and insulin resistance. The way people think about metabolic regulation has been changed, with the discovery of the transcriptional coactivator PGC-1α in 1998.

Reports developments in science as of December 2003. Support from scientists and funding agencies for 'open access' publications; Reevaluation of Food and Drug Administration of its position on the commercialization of milk, meat and other food products from cloned animals and their offspring; Sale of AIDS antiretroviral drugs by generic-drug manufactueres to some African and Caribbean countries.

The smallest capsid proteins (SCPs) of the human herpesviruses differ substantially in size and sequence and are thought to impart some unique aspects of infection to their respective viruses. We used electron cryomicroscopy and antibody labeling to show that the 8-kDa SCP of human cytomegalovirus is attached only to major capsid protein subunits of the hexons, not the pentons. Thus, the SCPs of different herpesviruses illustrate that a protein can evolve significantly in sequence, structure, and function, while preserving its role in the architecture of the virus by binding to a specific partner in a specific oligomeric state. [ABSTRACT FROM AUTHOR]