Optimization of tetrahydronaphthalene inhibitors of Raf with selectivity over hERG.

Investigations of a biaryl ether scaffold identified tetrahydronaphthalene Raf inhibitors with good in vivo activity; however these compounds had affinity toward the hERG potassium channel. Herein we describe our work to eliminate this hERG activity via alteration of the substituents on the benzoic amide functionality. The resulting compounds have improved selectivity against the hERG channel, good pharmacokinetic properties and potently inhibit the Raf pathway in vivo.

An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer.

The clinical development of an inhibitor of cellular proteasome function suggests that compounds targeting other components of the ubiquitin-proteasome system might prove useful for the treatment of human malignancies. NEDD8-activating enzyme (NAE) is an essential component of the NEDD8 conjugation pathway that controls the activity of the cullin-RING subtype of ubiquitin ligases, thereby regulating the turnover of a subset of proteins upstream of the proteasome. Substrates of cullin-RING ligases have important roles in cellular processes associated with cancer cell growth and survival pathways. Here we describe MLN4924, a potent and selective inhibitor of NAE. MLN4924 disrupts cullin-RING ligase-mediated protein turnover leading to apoptotic death in human tumour cells by a new mechanism of action, the deregulation of S-phase DNA synthesis. MLN4924 suppressed the growth of human tumour xenografts in mice at compound exposures that were well tolerated. Our data suggest that NAE inhibitors may hold promise for the treatment of cancer.

Kinetic isotope effects of nucleoside hydrolase from Escherichia coli.

rihC is one of a group of three ribonucleoside hydrolases found in Escherichia coli (E. coli). The enzyme catalyzes the hydrolysis of selected nucleosides to ribose and the corresponding base. A family of Vmax/Km kinetic isotope effects using uridine labeled with stable isotopes, such as 2H, 13C, and 15N, were determined by liquid chromatography/mass spectrometry (LC/MS). The kinetic isotope effects were 1.012+/-0.006, 1.027+/-0.005, 1.134+/-0.007, 1.122+/-0.008, and 1.002+/-0.004 for [1'-13C], [1-15N], [1'-2H], [2'-2H], and [5'-2H2] uridine, respectively. A transition state based upon a bond-energy bond-order vibrational analysis (BEBOVIB) of the observed kinetic isotope effects is proposed. The main features of this transition state are activation of the heterocyclic base by protonation of/or hydrogen bonding to O2, an extensively broken C-N glycosidic bond, formation of an oxocarbenium ion in the ribose ring, C3'-exo ribose ring conformation, and almost no bond formation to the attacking nucleophile. The proposed transition state for the prokaryotic E. coli nucleoside hydrolase is compared to that of a similar enzyme isolated from Crithidia fasciculata (C. fasciculata).

Association of Metabolic Syndrome with Body Fat Percent, Anthropometric Indices in 10 To 18 Year Old Adolescents.

BACKGROUND: Our aim was to evaluate the association of metabolic syndrome (MetS) and its components with body fat percentage (BFP) and anthropometric indicesin10 to 18year old adolescents. METHODS: This was a cross-sectional study conducted on 134 Tehranian adolescents, aged 10 to 18 years (66 boys and 68 girls) in 2007. The MetS definition proposed by Cook et al. was used. Logistic regression was used to determine the relationship of MetS and its components with body mass index (BMI), waist circumference (WC), waist to height ratio (WHtR), and BFP. Using the areas under the receiver operating characteristic (ROC) curve, the discriminatory ability of anthropometric measurements and BFP was evaluated. RESULTS: The mean±SD forage of boys and girls was14.5±2.3and13.0±2.9 years, respectively (P=0.001); the prevalence of MetS in these groups was 32.3 and6.5%, respectively (P=0.001). After adjusting for sex and physical activity, the highest odds ratios (95% CI) for MetS and hypertriglyceridemia were found for WC, 6.27 (2.63-14.94; P<0.05)and 3.14 (1.87-5.27; P<0.05), respectively, and those for low HDL-C and hypertension were found for BMI, 2.91 (1.73-4.90; P<0.05)and 2.26 (1.27-4.02; P=0.05), respectively. After adjusting for sex and physical activity, the highest area under ROC curve for MetS and hypertriglyceridemia was seen for WC (P=0.001), for hypertension it was seen for BMI (P=0.001), and for low HDL-C it was observed for both WC and BMI (P=0.001). CONCLUSIONS: In adolescents, WC was the best predictor of MetS and hypertriglyceridemia, BMI was the best predictor of hypertension, and WC and BMI were the best predictors for low HDL-C.

Discovery of a potent and orally bioavailable benzolactam-derived inhibitor of Polo-like kinase 1 (MLN0905).

This article describes the discovery of a series of potent inhibitors of Polo-like kinase 1 (PLK1). Optimization of this benzolactam-derived chemical series produced an orally bioavailable inhibitor of PLK1 (12c, MLN0905). In vivo pharmacokinetic-pharmacodynamic experiments demonstrated prolonged mitotic arrest after oral administration of 12c to tumor bearing nude mice. A subsequent efficacy study in nude mice achieved tumor growth inhibition or regression in a human colon tumor (HT29) xenograft model.

Design and optimization of potent and orally bioavailable tetrahydronaphthalene Raf inhibitors.

Inhibition of mutant B-Raf signaling, through either direct inhibition of the enzyme or inhibition of MEK, the direct substrate of Raf, has been demonstrated preclinically to inhibit tumor growth. Very recently, treatment of B-Raf mutant melanoma patients with a selective B-Raf inhibitor has resulted in promising preliminary evidence of antitumor activity. This article describes the design and optimization of tetrahydronaphthalene-derived compounds as potent inhibitors of the Raf pathway in vitro and in vivo. These compounds possess good pharmacokinetic properties in rodents and inhibit B-Raf mutant tumor growth in mouse xenograft models.