Integrating phenotypic small-molecule profiling and human genetics: the next phase in drug discovery

Abstract

Over the past decade, tremendous progress in high-throughput small molecule-screening methods has facilitated the rapid expansion of phenotype-based data. Parallel advances in genomic characterization methods have complemented these efforts by providing a growing list of annotated cell line features. Together, these developments have paved the way for feature-based identification of novel, exploitable cellular dependencies, subsequently expanding our therapeutic toolkit in cancer and other diseases. Here, we provide an overview of the evolution of phenotypic small-molecule profiling and discuss the most significant and recent profiling and analytical efforts, their impact on the field, and their clinical ramifications. We additionally provide a perspective for future developments in phenotypic profiling efforts guided by genomic science.

Keywords: cell line profiling; genotype–phenotype; small molecule.

Figure 1

Cumulative increase in the number of papers in the literature focused on profiling experiments. Results were achieved by using the query “phenotypic profiling”, followed by manual annotation of each of the 100 results for their applicability to this metric. Papers were then labeled as specifically involving small-molecule profiling. We then added the literature cited in this review that did not use the query term to the total numbers.

Figure 2

The evolution of a profiling matrix over the course of the last twenty years. The three axes represent perturbations (small-molecule or genetic), cell lines or cell states profiled, and genetic features characterized. 1: a typical high-throughput screening campaign. 2: experimentation exemplified by the NCI-60 collection [5]. 3: the inclusion of gene-expression data in profiling experiments [72, 73]. 4: profiling of a small number of related compounds across many cell lines [21]. 5: the transpose of 4, representing the profiling of many compounds across a small number of related cell lines [22] (not in version 2). 6: early attempts to expand the genetic features characterized across profiled cell lines [26]. 7: efforts to expand the matrix to incorporate many cell lines, many genetic features, and now many compounds [6-8].