Characterizing the relationship between the chemical structures of drugs and their activities on primary cultures of pediatric solid tumors

Better drugs are required to manage pediatric cancers. A high-throughput screen of drugs in primary cultures derived from orthotopic patient-derived xenografts (O-PDX) of pediatric solid tumours has been recently published. Here we analyzed these data sets to find out whether it is possible to leverage them for identifying new drug leads in a phenotypic manner. We found that drugs bearing a higher number of heterocyclic rings, two carbon-hetero bonds and halogens are associated to submicromolar potency in alveolar rhabdomyosarcoma and osteosarcoma O-PDXs. Furthermore, Murcko scaffolds 1-cyclopentyl-octahydro-1H-indene and tetradecahydroanthracene can be utilized as starting scaffolds to selectively optimize potency against osteosarcoma since drugs bearing this scaffold displayed superior O-PDX culture potency. Lastly, we have generated QSAR (Quantitative Structure-Activity Relationship) models able to predict the potency of drugs on each O-PDX tumor. To permit their use to guide drug repositioning on these 30 O-PDX cell cultures, we are providing a user-friendly web server implementing these QSAR models at https://rnewbie.shinyapps.io/Shobek-master