Small-Molecule Ligands that Bind the RET Receptor Activate Neuroprotective Signals Independent of but Modulated by Coreceptor GFR1.

Glial cell line-derived neurotrophic factor (GDNF) binds the GFR1 receptor, and the GDNF-GFR1 complex binds to and activates the transmembrane RET tyrosine kinase to signal through intracellular Akt/Erk pathways. To dissect the GDNF-GFR1-RET signaling complex, agents that bind and activate RET directly and independently of GFR1 expression are valuable tools. In a focused naphthalenesulfonic acid library from the National Cancer Institute database, we identified small molecules that are genuine ligands binding to the RET extracellular domain.