Best Practices in Compound Management for Preserving Compound Integrity and Accurately Providing Samples for Assays

Abstract

Preserving the integrity of the compound collection and providing high-quality materials for drug discovery in an efficient and cost-effective manner are 2 major challenges faced by compound management (CM) at Bristol-Myers Squibb (BMS). The demands on CM include delivering hundreds of thousands of compounds a year to a variety of operations. These operations range from single-compound requests to hit identification support and just-in-time assay plate provision for lead optimization. Support needs for these processes consist of the ability to rapidly provide compounds as solids or solutions in a variety of formats, establishing proper long-and short-term storage conditions and creating appropriate methods for handling concentrated, potent compounds for delivery to sensitive biological assays. A series of experiments evaluating the effects of processing compounds with volatile solvents, storage conditions that can induce freeze/thaw cycles, and the delivery of compounds were performed. This article presents the results of these experiments and how they affect compound integrity and the accuracy of compound management processes. (Journal of Biomolecular Screening 2009:476-484)

Enhancing Reproducibility in Cancer Drug Screening: How Do We Move Forward?

“…Several factors could introduce variability in the results of in vitro cell-based assays. It is important to establish best practices on how the chemical compound collection is managed, maintained, and delivered to the assay plates for screening [18]. Critical factors include compound handling to ensure accuracy in the amount of the compound transferred to the master solution, maximal solubility in the solvent used (usually DMSO), optimal storage conditions to ensure compound integrity, and to minimize liquid loss through evaporation or leaching of the test compounds through the storage containers [19].…”

Recent development in high-throughput bioanalytical support forin vitroADMET profiling

“…In addition, STARScreen has the ability to parse data files from different vendors into a single, standardized data format (analytical information markup language [160]) for easy review, process, archival and retrieval. Furthermore, the structural integrity [161] results for the profiled compounds are accessed automatically by STARScreen to validate the ADMET assay results, by confirming the identity and purity of the compounds after storage and dispatch through LC-MS analyses, as described previously by the compound management department of Bristol-Myers Squibb [162,163]. Separately, Luippold et al [164] presented a similar integration tool, which goes a step further by also incorporating the in vitro ADMET assay liquid handling in addition to all the bioanalytical tasks.…”

Dispensing Processes Impact Apparent Biological Activity as Determined by Computational and Statistical Analyses

“…Processes like tip-based and acoustic dispensing have a profound influence on estimates of compound activity. Several independent studies of high-throughput screening (HTS) show that the two techniques generate conflicting results [1], [2], [3], [4], [5]. The difference in results may mean missing important lead compounds, following dead-ends and developing inappropriate compounds for activity optimization.…”

“…Broadly speaking, the IC 50 values derived using tip-based serial dilution and dispensing tend to be greater (i.e., show lower potency) than IC 50 values derived using acoustic dispensing. Some compounds appeared hundreds of times more active with the acoustic process [1], [2], [3], [4]. We now address how these errors may affect computational models and propagate poor data in both proprietary and public databases, the result of which is likely to misdirect drug design.…”