Updated project metadata. Targeted Protein Degradation (TPD) utilizes small molecules to direct proteins towards E3 ubiquitin ligases for degradation, but is limited by the small number of ligases accessible for this approach. We introduce SP3N, a novel degrader targeting FKBP12, designed with a simple structure that integrates a FKBP12 ligand with a degradation-inducing alkylamine tail. Through comprehensive target identification, we show that SP3N acts as a prodrug, converting its alkylamine to an active aldehyde that engages the SCF FBXO22 ligase for FKBP12's degradation via covalent attachment to FBXO22's Cys326, essential for the degradation process. This mechanism, also applicable to NSD2 and XIAP degraders, presents a new, broadly applicable TPD method involving alkylamine-based tethering and covalent modification of FBXO22.