RVX-297, a BET Bromodomain Inhibitor, Has Therapeutic Effects in Preclinical Models of Acute Inflammation and Autoimmune Disease.

Bromodomain (BD) and extra-terminal domain containing proteins (BET) are chromatin adapters that bind acetylated histone marks via two tandem BDs, BD1 and BD2, to regulate gene transcription. BET proteins are involved in transcriptional reprogramming in response to inflammatory stimuli. BET BD inhibitors (BETis) that are nonselective for BD1 or BD2 have recognized anti-inflammatory properties in vitro and counter pathology in models of inflammation or autoimmune disease.

Lifestyle transitions in plant pathogenic Colletotrichum fungi deciphered by genome and transcriptome analyses.

Colletotrichum species are fungal pathogens that devastate crop plants worldwide. Host infection involves the differentiation of specialized cell types that are associated with penetration, growth inside living host cells (biotrophy) and tissue destruction (necrotrophy). We report here genome and transcriptome analyses of Colletotrichum higginsianum infecting Arabidopsis thaliana and Colletotrichum graminicola infecting maize.

Insights into evolution of multicellular fungi from the assembled chromosomes of the mushroom Coprinopsis cinerea (Coprinus cinereus).

The mushroom Coprinopsis cinerea is a classic experimental model for multicellular development in fungi because it grows on defined media, completes its life cycle in 2 weeks, produces some 10(8) synchronized meiocytes, and can be manipulated at all stages in development by mutation and transformation. The 37-megabase genome of C. cinerea was sequenced and assembled into 13 chromosomes.

Development of an intravenous formulation of SU010382 (prodrug of SU5416, an anti-angiogenesis agent).

SU5416, the first in a new class of anti-angiogenesis agents, is an insoluble and neutral molecule which requires a formulation containing Cremophor EL, ethanol, and polyethylene glycol. SU010382, a prodrug of SU5416, was designed as N-Mannich base to provide a basic handle that could be exploited to increase the compound's solubility. Though an increase in solubility was obtained, the inherent hydrolytic instability of SU010382 presented a major challenge in formulation development.

High-performance liquid chromatographic method for determination of reversible isomers of SU5416.

SU5416 shows light-induced reversible geometric isomerism. A simple, reliable, isocratic HPLC method using an UV-vis detector at lambda(425nm) was developed. The method provides efficient (R(S)=3.

Reversible Z-E isomerism and pharmaceutical implications for SU5416.

SU5416 (Z-isomer), the first in its class of angiogenesis inhibitors, in solution converts to the E-isomer following light exposure and reverts to the Z-isomer in the dark. Kinetics of this Z-E isomerism in pharmaceutical media is reported. Analytical solutions need light protection at 5 degrees C to maintain integrity.

Powder-in-bottle formulation of SU011248. Enabling rapid progression into human clinical trials.

SU011248 is an oral, multitargeted receptor tyrosine kinase inhibitor (anti PDGFR, VEGFR, Kit, and Flt3) for the treatment of solid tumors. The powder-in-bottle (PIB) approach was used to accelerate development and introduction into Phase I clinical trials. This approach consists of extemporaneously compounding the active pharmaceutical ingredient (API) into a solution or a suspension in the clinic prior to oral administration.

Inhibition of constitutively active forms of mutant kit by multitargeted indolinone tyrosine kinase inhibitors.

Mutations in the proto-oncogene c-kit, including point mutations, deletions, or duplications in the negative regulatory juxtamembrane (JM) domain or point mutations in the catalytic domain, have been observed in human and canine cancers and often result in constitutive activation of Kit in the absence of ligand binding. To identify a receptor tyrosine kinase (RTK) inhibitor capable of blocking the function of mutant Kit, we evaluated 3 indolinones (SU11652, SU11654, and SU11655) that act as competitive inhibitors of adenosine triphosphate binding to several members of the split kinase family of RTKs, including VEGFR, FGFR, PDGFR, and Kit. Mast cell lines expressing either wild-type (WT) Kit, a point mutation in the JM domain, a tandem duplication in the JM domain, or a point mutation in the catalytic domain were used for these studies.