Biomedical subjects
Publications and source records attributed to John Eksterowicz.
Novel analogs of (-)-saframycin A are described. The analogs are shown to be potent inhibitors of the in vitro growth of several tumor cells in a broad panel and promising as leads for further optimization. The first in vivo studies in a solid tumor model (HCT-116) reveal potent antitumor activity with associated toxicity of daily administration.
As a continuation of our efforts to discover novel apoptosis inducers as anticancer agents using a cell-based caspase HTS assay, 2-phenyl-oxazole-4-carboxamide derivatives were identified. The structure-activity relationships of this class of molecules were explored. Compound 1k, with EC(50) of 270 nM and GI(50) of 229 nM in human colorectal DLD-1 cells, was selected and demonstrated the ability to cleave PARP and displayed DNA laddering, the hallmarks of apoptosis. Compound 1k showed 63% tumor growth inhibition in human colorectal DLD-1 xenograft mouse model at 50 mpk, bid.
The performance of docking studies into protein active sites constructed by homology model building was investigated using CDK2 and factor VIIa screening data sets. When the sequence identity between model and template near the binding site area is greater than approximately 50%, roughly 5 times more active compounds are identified than would be found randomly. This performance is comparable to docking to crystal structures.
Molecules with similar shapes and features often have similar biological activity. Several computational approaches search chemical databases for new leads or templates based on overall molecular shape similarity. However, active molecules often present critical subshapes that are required for binding, which may be missed by comparing overall shape similarity. We present a new approach to compare molecular shapes of different sizes and to calculate subshape similarity. We developed a skeletal representation of the shape which is topologically unrelated to covalent chemical connectivity. This simplifies rotational and translational sampling. We test initial possible alignments by matching similar triangles. This triangle-matching filter rapidly eliminates most geometrically impossible matches. Surviving matches are filtered further in successive stages. These stages involve direction, feature, and shape matching procedures. Our approach is applied to several situations demonstrating lead discovery and evolution.