Synergistic Effects of Stereochemistry and Appendages on the Performance Diversity of a Collection of Synthetic Compounds

• DOI: 10.1021/jacs.8b07319
• Publication Date: 2018-08-22T16:08:48Z
• Authors: Bruno Melillo; Jochen Zoller; Bruce K. Hua; Oscar Verho; Jannik C. Borghs; Shawn D. Nelson; Micah Maetani; Mathias J. Wawer; Paul A. Clemons; Stuart L. Schreiber
• Keywords: Appendage

Target- and phenotype-agnostic assessments of biological activity have emerged as viable strategies for prioritizing scaffolds, structural features, synthetic pathways in screening sets, with the goal increasing performance diversity. Here, we describe synthesis a small library functionalized stereoisomeric azetidines its annotation by "cell painting," multiplexed, high-content imaging assay capable measuring many hundreds compound-induced changes cell morphology quantitative unbiased fashion. Using this approach, systematically compare degrees to which core scaffold's activity, inferred from effects on morphology, is affected variations stereochemistry appendages. We show that stereoisomerism appendage diversification can produce similar magnitude, concurrent use these results broader sampling activity.