Using a live cell, high-throughput caspase-3 activator assay, we have identified a novel series of 4-anilinoquinazolines as inducers of apoptosis. In this report, we discuss the discovery of 2-chloro-N-(4-methoxyphenyl)-N-methylquinazolin-4-amine, compound 2b (EP128265, MPI-0441138) as a highly active inducer of apoptosis (EC50 for caspase activation of 2 nM) and as a potent inhibitor of cell proliferation (GI50 of 2 nM) in T47D cells. Compound 2b inhibited tubulin polymerization, was effective in cells overexpressing ABC transporter Pgp-1, and was efficacious in the MX-1 human breast and PC-3 prostate cancer mouse models. In contrast to the SAR of 4-anilinoquinazolines as EGFR kinase inhibitors, the methyl group on the nitrogen linker was essential for the apoptosis-inducing activity of 4-anilinoquinazolines and substitution in the 6- and 7-positions of the quinazoline core structure decreased potency.

A series of tetrahydropyranyl (THP) derivatives has been developed as potent inhibitors of isoprenylcysteine carboxyl methyltransferase (ICMT) for use as anticancer agents. Structural modification of the submicromolar hit compound 3 led to the potent 3-methoxy substituted analogue 27. Further SAR development around the THP ring resulted in an additional 10-fold increase in potency, exemplified by analogue 75 with an IC(50) of 1.3 nM. Active and potent compounds demonstrated a dose-dependent increase in Ras cytosolic protein. Potent ICMT inhibitors also reduced cell viability in several cancer cell lines with growth inhibition (GI(50)) values ranging from 0.3 to >100 μM. However, none of the cellular effects observed using ICMT inhibitors were as pronounced as those resulting from a farnesyltransferase inhibitor.

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Objective:Survey of serum concentrations of S100 protein and NSE in patients with acute cerebral infarction. To understand the relationship between serum S100 protein and NSE concentrations with some other risk factors such as age, sex, Glasgow Coma Scale, cerebral lesion volume on computerized tomography. Subjects and Methods: Study of 90 hospitalized patients with cerebral infarction at ICU of Hue Central Hospital and 100 controls. Data was collected through medical records of patients with acute cerebral infarction and control. The study method was acrossectional and descriptive. Data was analysed by medical statistics and processed by the SPSS 19.0 software.Results: In our study group of patients with average age was 68.3 ± 13.1. (Min: 32, Max: 90). Age of majority from 61 to 80 years (48.9%) patients who were the retired elderly. The average concentration of S100 protein and NSE in patient group was 1.489 ± 2.663 (micrograms/L); 38.36 ± 34.46(ng/mL), respectively.The greater volume of lesions was, the higher the concentration of S100 protein and NSE was. There was a agreement correlation between the S100 protein and NSE with lesion volume, the correlation equations respectively: y = 20.6x + 67.71 (n = 90; r = 0.397; p <0.01); y= 1.441x + 43.104 (n = 90; r = 0.359; p <0.01). Cut-off value to predict the survival of S100 protein and NSE in this study respectively 0.21 mcg/l and 20.45ng/ml. Predictive value of survival (death) of S100 protein is higher than NSE. Conclusion: The average concentration of S100 protein and NSE in patient group was 1.489 ± 2.663 (micrograms/L); 38.36 ± 34.46(ng/mL), respectively. Cut-off value to predict the survival of S100 protein and NSE in this study respectively 0.21 mcg/l and 20.45ng/ml. Predictive value of survival of S100 protein is higher than NSE. There is positive correlation between NSE and S100 protein with lesion volume. S100 protein and NSE can be used to predict and monitor disease progression and the volume of brain lesions. Keywords: Stroke, acute cerebral infarction, S100 protein, NSE.

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