Small-molecule discovery in the pancreatic beta cell.

The pancreatic beta cell is the only cell type in the body responsible for insulin secretion, and thus plays a unique role in the control of glucose homeostasis. The loss of beta-cell mass and function plays an important role in both type 1 and type 2 diabetes. Thus, using chemical biology to identify small molecules targeting the beta cell could be an important component to developing future therapeutics for diabetes.

Emerging diabetes therapies: Bringing back the β-cells.

Background: Stem cell therapies are finally coming of age as a viable alternative to pancreatic islet transplantation for the treatment of insulin-dependent diabetes. Several clinical trials using human embryonic stem cell (hESC)-derived β-like cells are currently underway, with encouraging preliminary results. Remaining challenges notwithstanding, these strategies are widely expected to reduce our reliance on human isolated islets for transplantation procedures, making cell therapies available to millions of diabetic patients.

When Small Molecules Are Like Real Estate: It's All about Location, Location, Location.

In this issue of Cell Chemical Biology, Park et al. (2018) demonstrate that targeting apoptazole, an Hsp70 inhibitor, to mitochondria induces apoptosis by a distinct mechanism of action different from unmodified apoptazole, which accumulates in the lysosome. These results highlight the power of subcellular localization in small-molecule selectivity.

The Power of Sophisticated Phenotypic Screening and Modern Mechanism-of-Action Methods.

The enthusiasm for phenotypic screening as an approach for small-molecule discovery has increased dramatically over the last several years. The recent increase in phenotype-based discoveries is in part due to advancements in phenotypic readouts in improved disease models that recapitulate clinically relevant biology in cell culture. Of course, a major historical barrier to using phenotypic assays in chemical biology has been the challenge in determining the mechanism of action (MoA) for compounds of interest.

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

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.

A small-molecule inducer of PDX1 expression identified by high-throughput screening.

Pancreatic and duodenal homeobox 1 (PDX1), a member of the homeodomain-containing transcription factor family, is a key transcription factor important for both pancreas development and mature β cell function. The ectopic overexpression of Pdx1, Neurog3, and MafA in mice reprograms acinar cells to insulin-producing cells. We developed a quantitative PCR-based gene expression assay to screen more than 60,000 compounds for expression of each of these genes in the human PANC-1 ductal carcinoma cell line.