Large-Scale Chemical Similarity Networks for Target Profiling of Compounds Identified in Cell-Based Chemical Screens
Fig 4
Integration of CSNAP with knowledge databases for mitotic target prediction and phenotypic target validation.
(A) Mitotic compound chemical similarity network. CSNAP analysis of 212 mitotic compounds yielded 85 chemical similarity clusters representing diverse chemotypes, only 21 compounds were not clustered into annotated similarity graphs. (B) LTIF analysis of CSNAP mitotic target predictions. The target spectrum identified four major classes of targets from the top peaks including fatty acid desaturase (SCD), ABL kinase (ABL1), phosphatase (PTPN) and tubulin (TUBB). An independent LTIF analysis of each target class is presented in S2 Fig. (C) Mitotic compound deconvolution. Target associated chemical similarity sub-networks of four predicted targets (SCD, ABL1, PTPN and TUBB) were “pulled-down” from the mitotic CSN. For each cluster, at least one mitotic compound connected to one or more reference nodes with Tc threshold> 0.7. Note that the predicted SCD and ABL1 compounds display over-lapping neighbors, indicating that the predicted targets may be modulated by both compound sets. (D) Phenotypic validation of predicted mitotic targets. Asynchronous HeLa cells were treated with indicated compounds for 24 hours, fixed and stained for DNA and Tubulin. The observed compound-induced cell division defects were compared to target gene expression knockdown defects within the MitoCheck database. All compounds matched the previously characterized phenotypes associated with knockdown of target protein expression. See S6 Fig for complete compound-induced phenotypes.