Disease allele-dependent small-molecule sensitivities in blood cells from monogenic diabetes

Abstract

Even as genetic studies identify alleles that influence human disease susceptibility, it remains challenging to understand their functional significance and how they contribute to disease phenotypes. Here, we describe an approach to translate discoveries from human genetics into functional and therapeutic hypotheses by relating human genetic variation to small-molecule sensitivities. We use small-molecule probes modulating a breadth of targets and processes to reveal disease allele-dependent sensitivities, using cells from multiple individuals with an extreme form of diabetes (maturity onset diabetes of the young type 1, caused by mutation in the orphan nuclear receptor HNF4α). This approach enabled the discovery of small molecules that show mechanistically revealing and therapeutically relevant interactions with HNF4α in both lymphoblasts and pancreatic β-cells, including compounds that physically interact with HNF4α. Compounds including US Food and Drug Administration–approved drugs were identified that favorably modulate a critical disease phenotype, insulin secretion from β-cells. This method may suggest therapeutic hypotheses for other nonblood disorders.

Autosis is a Na + ,K + -ATPase–regulated form of cell death triggered by autophagy-inducing peptides, starvation, and hypoxia–ischemia

“…Chemical screening and CSEA were performed as previously described (35). Details of screening methodology and analyses are provided in SI Materials and Methods.…”

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

“…More disease-focused work also attempted to discover gene-small molecule interactions [21]. Using patient-derived LCLs from 18 members of a MODY1 (maturity-onset diabetes of the young 1, caused by mutation in the transcription factor HNF4a) family, the effects of nearly 4,000 bioactive compounds and clinically used drugs were tested on these cells using an ATP-based viability readout.…”

Organic synthesis toward small-molecule probes and drugs

“…For example, correlations between genetic variation and sensitivity toward highly selective small-molecule probes may facilitate the development of drugs tailored for the genetic features of disease associated with individual patients. Although this is perhaps most evident in diseases such as cancer where the penetrance of somatic mutations is often high (22,23), new approaches have been described that reveal such correlations in heritable disease as well (24).…”