KDM3B inhibitors disrupt the oncogenic activity of PAX3-FOXO1 in fusion-positive rhabdomyosarcoma
In “KDM3B inhibitors disrupt the oncogenic activity of PAX3-FOXO1 in fusion-positive rhabdomyosarcoma,” researchers screened thousands of drug compounds in cell culture and a mouse model of fusion-positive rhabdomyosarcoma (FP-RMS). FP-RMS is driven primarily by the fusion of two genes into one called PAX3-FOXO1. Through their screening, they identified a previously unstudied compound called P3FI-63 and with further investigation determined that it works through proteins called histone lysine demethylases (KDMs) with the greatest affinity for KDM3B. Additionally, they found that a structurally similar drug, P3FI-90, had improved solubility and potency. They were then able to demonstrate that P3FI-90 decreases the growth of FP-RMS cells in vitro and in mice through downregulating PAX3-FOXO1 activity. Although this is a study very early in the drug development process, the results indicate that this could be a therapeutic approach for FP-RMS.
In conclusion, P3FI-90 inhibits multiple KDMs with highest selectivity for KDM3B that can be further developed for the therapy of highly malignant FP-RMS and possibly other “transcriptionally addicted” cancers.