CRBN(FLT3)-8

CRBN(FLT3)-8 is a proteolysis-targeting chimera (PROTAC) designed to induce the degradation of FMS-like tyrosine kinase 3 (FLT3). It is chemically derived from the FLT3 inhibitor gilteritinib and functions by recruiting the Cereblon (CRBN) E3 ubiquitin ligase to the FLT3 protein, leading to its polyubiquitination and subsequent degradation by the 26S proteasome. This approach is specifically intended to overcome resistance in acute myeloid leukemia (AML) caused by the FLT3-F691L gatekeeper mutation. While traditional type I FLT3 inhibitors like gilteritinib fail to suppress MAPK signaling in FLT3-F691L cells due to kinase-independent functions of the mutated protein, CRBN(FLT3)-8 effectively depletes the FLT3 protein itself, thereby inhibiting both its kinase activity and its non-kinase-mediated signaling pathways, such as Grb2-dependent MAPK activation. The compound was developed through a collaborative effort involving researchers at Cincinnati Children's Hospital Medical Center and the National Institutes of Health (NCATS and NCI).