KB02-SLF is a PROTAC-based nuclear FKBP12 degrader, also known as a molecular glue, that facilitates the degradation of nuclear FKBP12 by covalently modifying DCAF16, an E3 ligase. SLF acts as a linker, binding to the ubiquitin E3 ligase ligand KB02, thus forming KB02-SLF[1] and enhancing the longevity of protein degradation in biological systems.

FLAG-tagged variants of FKBP12 (FLAG-FKBP12) or FKBP12 with a C-terminal nuclear localization sequence (FLAG-FKBP12_NLS) in HEK293T cells to provide cell models for evaluating cytosolic-and nuclear-localized E3-mediated degradation pathways, respectively. KB02-SLF promotes a substantial reduction in nuclear FKBP12 that is sustained across a 4-72h time frame. Cell imaging studies confirms the selective loss of nuclear-localized FKBP12 in KB02-SLF-treated cells. KB02-SLF promotes the loss of FKBP12_NLS across a concentration of ~0.5-5μM, but shows varied reductions in activity at higher concentrations. The degradation of FKBP12_NLS induced by KB02-SLF is mediated by DCAF16[1].