Abstract IA2: Accelerating natural product discovery with multivariate image-based screening

Abstract

Abstract Multiparameter phenotypic profiling has emerged as a powerful tool for characterizing small molecules and their effects on complex biological systems. In particular, the union of high-throughput screening technologies with automated microscopy and image processing has enabled the development of multiparameter image-based profiling techniques (also called “cytological profiling”), in which cells are imaged in multiwell plate format using automated fluorescence microscopy and the resulting images are quantified in terms of various descriptors, or “features.” Rather than focusing on a specific phenotype or biological endpoint, CP strategies employ multiple cytological probes that are selected to cover a wide range of biological pathways. Although CP has been used successfully to classify diverse bioactive compounds, its application in the area of natural products (NP) discovery has been limited. Here we describe the use of cytological profiling to discover natural products with novel mechanisms of action (MOAs). The goal of this project is to invert the NP discovery process from the traditional approach, where compound identification and function are the final steps in the discovery process, to a new paradigm where identities and functions of active constituents are determined directly from primary screening data and lead compounds are selected based on chemical and biological novelty prior to isolation and full structural characterization. Futhermore, the integration of CP fingerprints with metabolomics data allows us to rapidly associate compounds with phenotypes and prioritize unique chemistries for follow up. Citation Format: Scott M. Lokey. Accelerating natural product discovery with multivariate image-based screening [abstract]. In: Proceedings of the AACR Special Conference on Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations; 2012 Jun 27-30; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2012;72(13 Suppl):Abstract nr IA2.