The growth of solid tumors is dependent on the continued stimulation of endothelial cell proliferation and migration resulting in angiogenesis. The angiogenic process is controlled by a variety of factors of which the vascular endothelial growth factor (VEGF) pathway and its receptors play a pivotal role. Small-molecule inhibitors of VEGF receptors (VEGFR) have been shown to inhibit angiogenesis and tumor growth in preclinical models and in clinical trials. A novel nicotinamide, AMG 706, was identified as a potent, orally bioavailable inhibitor of the VEGFR1/Flt1, VEGFR2/kinase domain receptor/Flk-1, VEGFR3/Flt4, platelet-derived growth factor receptor, and Kit receptors in preclinical models. AMG 706 inhibited human endothelial cell proliferation induced by VEGF, but not by basic fibroblast growth factor in vitro, as well as vascular permeability induced by VEGF in mice. Oral administration of AMG 706 potently inhibited VEGF-induced angiogenesis in the rat corneal model and induced regression of established A431 xenografts. AMG 706 was well tolerated and had no significant effects on body weight or on the general health of the animals. Histologic analysis of tumor xenografts from AMG 706-treated animals revealed an increase in endothelial apoptosis and a reduction in blood vessel area that preceded an increase in tumor cell apoptosis. In summary, AMG 706 is an orally bioavailable, well-tolerated multikinase inhibitor that is presently under clinical investigation for the treatment of human malignancies. (Cancer Res 2006; 66(17): 8715-21)

Background: Mutant-selective IDH1 inhibitors are potential cancer therapeutics, but the mechanistic basis for their selectivity is not yet well understood. Results: Inhibitor binding modes and kinetic mechanisms were characterized. Conclusion:The inhibitors selectively inhibit mutant IDH1 by interacting with a magnesium-binding residue. Significance: Targeting metal-binding residues with drug-like small molecules is a feasible strategy for IDH1 inhibition.

In mammalian cells, the aurora kinases (aurora-A, -B, and -C) play essential roles in regulating cell division.

Inhibition of angiogenesis is a promising and clinically validated approach for limiting tumor growth and survival. The receptor tyrosine kinase Tie-2 is expressed almost exclusively in the vascular endothelium and is required for developmental angiogenesis and vessel maturation. However, the significance of Tie-2 signaling in tumor angiogenesis is not well understood. In order to evaluate the therapeutic utility of inhibiting Tie-2 signaling, we developed a series of potent and orally bioavailable small molecule Tie-2 kinase inhibitors with selectivity over other kinases, especially those that are believed to be important for tumor angiogenesis. Our earlier work provided pyridinyl pyrimidine 6 as a potent, nonselective Tie-2 inhibitor that was designed on the basis of X-ray cocrystal structures of KDR inhibitors 34 (triazine) and 35 (nicotinamide). Lead optimization resulted in pyridinyl triazine 63, which exhibited >30-fold selectivity over a panel of kinases, good oral exposure, and in vivo inhibition of Tie-2 phosphorylation.

The present study aimed to retrospectively evaluate the usefulness of cell counter-based parameters and formulas in beta-thalassemia trait (BTT) detection. The study included 170 BTT cases (hemoglobin [Hb]A(2) >4.0% [0.04]) and 30 non-BTT cases (HbA(2), 2.3%-3.5% [0.02-0.04]). Depending on the hemoglobin level and iron deficiency, the BTT group was further classified into classic BTT (n = 112) and BTT with iron deficiency anemia (n = 58). The RBC count, MCH, MCV, RDW, and Shine and Lal, Mentzler, Srivastava, England and Fraser, Ricerca, and Green indexes were applied. For the first time in the population of India, these 10 cell counter parameters and manual formulas were compared with high-performance liquid chromatography-derived HbA2 levels for deriving a cost-effective alternative method; and receiver operating characteristic curves were applied. We found that the Shine and Lal, Srivastava, and Mentzler indexes, MCV, and MCH have better discriminative function than the RBC count and red cell distribution width and their related formulas.