Reduction of Progranulin-Induced Breast Cancer Stem Cell Propagation by Sortilin-Targeting Cyclotriazadisulfonamide (CADA) Compounds
Karoline Berger, Eva Pauwels, Gabrielle T. Parkinson, Göran Landberg, Truc Le, Violeta G. Demillo, Liezel A. Lumangtad, Dylan E. Jones, Md Azizul Islam, Ryan K Olsen, Topprasad Kapri, Amarawan Intasiri, Kurt Vermeire, Sara Rhost, Thomas W. Bell
Abstract
Cyclotriazadisulfonamide (CADA) compounds selectively down-modulate two human proteins of potential therapeutic interest, cluster of differentiation 4 (CD4) and sortilin. Progranulin is secreted from some breast cancer cells, causing dedifferentiation of receiving cancer cells and cancer stem cell proliferation. Inhibition of progranulin binding to sortilin, its main receptor, can block progranulin-induced metastatic breast cancer using a triple-negative in vivo xenograft model. In the current study, seven CADA compounds (CADA, VGD020, VGD071, TL020, TL023, LAL014, and DJ010) were examined for reduction of cellular sortilin expression and progranulin-induced breast cancer stem cell propagation. In addition, inhibition of progranulin-induced mammosphere formation was examined and found to be most significant for TL020, TL023, VGD071, and LAL014. Full experimental details are given for the synthesis and characterization of the four new compounds (TL020, TL023, VGD071, and DJ010). Comparison of solubilities, potencies, and cytotoxicities identified VGD071 as a promising candidate for future studies using mouse breast cancer models.