Identifying Compound-Target Associations by Combining Bioactivity Profile Similarity Search and Public Databases Mining

Molecular target identification is of central importance to drug discovery. Here, we developed a computational approach, named bioactivity profile similarity search (BASS), for associating targets to small molecules by using the known target annotations of related compounds from public databases. To evaluate BASS, a bioactivity profile database was constructed using 4296 compounds that were commonly tested in the US National Cancer Institute 60 human tumor cell line anticancer drug screen (NCI-60). Each compound was used as a query to search against the entire bioactivity profile database, and reference compounds with similar bioactivity profiles above a threshold of 0.75 were considered as neighbor compounds of the query. Potential targets were subsequently linked to the identified neighbor compounds by using the known targets o

Tubulin-binding dibenz[c,e]oxepines: Part 2 Structural variation and biological evaluation as tumour vasculature disrupting agents

5,7-Dihydro-3,9,10,11-tetramethoxybenz[c,e]oxepin-4-ol 1, prepared from a dibenzyl ether precursor via Pd-catalysed intramolecular direct arylation, possesses broad-spectrum in vitro cytotoxicity towards various tumour cell lines, and induces vascular shutdown, necrosis and growth delay in tumour xenografts in mice at sub-toxic doses. The biological properties of 1 and related compounds can be attributed to their ability to inhibit microtubule assembly at the micromolar level, by binding reversibly to the same site of the tubulin αβ-heterodimer as colchicine 2 and the allocolchinol, N-acetylcolchinol 4

Pharmacological inhibitors of glycogen synthase kinase 3

Three closely related forms of glycogen synthase kinase 3 (GSK-3alpha, GSK-3beta and GSK-3beta2) have a major role in Wnt and Hedgehog signaling pathways and regulate the cell-division cycle, stem-cell renewal and differentiation, apoptosis, circadian rhythm, transcription and insulin action. A large body of evidence supports speculation that pharmacological inhibitors of GSK-3 could be used to treat several diseases, including Alzheimer's disease and other neurodegenerative diseases, bipolar affective disorder, diabetes, and diseases caused by unicellular parasites that express GSK-3 homologues. The toxicity, associated side-effects and concerns regarding the absorption, distribution, metabolism and excretion of these inhibitors affect their clinical potential. More than 30 inhibitors of GSK-3 have been identified. Seven of these have been co-crystallized with GSK-3beta and all localize within the ATP-binding pocket of the enzyme. GSK-3, as part of a multi-protein complex that contains proteins such as axin, presenilin and beta-catenin, contains many additional target sites for specific modulation of its activity