Chemical Phenomics Initiative to Drive Therapeutic Target Discovery
Charles Williams
Charles Hong
10.6084/m9.figshare.12149769.v1
https://tagc2020.figshare.com/articles/poster/Chemical_Phenomics_Initiative_to_Drive_Therapeutic_Target_Discovery/12149769
<p>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.</p>
2020-04-20 22:28:39
Drug discovery
Chemical Biology
PheWAS
Computational Biology
Computational Biology
Molecular Biology
Developmental Biology