Chemical Phenomics Initiative to Drive Therapeutic Target Discovery

2020-04-20T22:28:39Z (GMT) by Charles Williams Charles Hong

Chemical genetics involves the discovery, development and use of chemical probes for interrogation of biological processes and for translational discoveries. In a manner analogous to classic forward mutagenesis screens, the Hong lab has conducted an unbiased, high-throughput chemical screen for small molecules that specifically modulate early embryonic development in zebrafish, and has carried out the follow-up task of identifying the pharmacological targets of a number of developmental modulators. Using this target-agnostic, “high content” phenotypic screening platform, we have discovered novel BMP, Wnt and hedgehog inhibitors, as well as first-in-class modulators of cell signaling components. Moreover, since disturbances in developmental pathways play central role in the pathogenesis of many human illnesses, small molecules that selectively target them have significant translational potential. Yet the complexity and unbiased nature of phenotypic screens make the crucial follow-up task of identifying the biologically relevant target of each hit very challenging. Leveraging the available molecular genetic information on early zebrafish embryogenesis, we have developed ZePASS (Zebrafish Phenotypic Anatomical Similarity System), an unbiased deep learning method to map the actions of small molecules and accelerate target identification. Finally, we are leveraging UK Biobank phenotype-genotype database to identify the clinical phenotypes associated with naturally occurring human genetic variations in the target genes, and then utilize these associations to ultimately guide therapeutic development for important unmet clinical needs. Finally, digitally annotated results of chemical screens and target deconvolution will be made available to the broader scientific community via a searchable, online database named Chemical Phenomics Initiative.