Structure-based design of novel JAK2 degraders. Guided by the novel crystal structures of JAK2 kinase domain bound to type I JAK1/JAK2 inhibitors ruxolitinib and baricitinib, PROTACs were designed by modifying these JAK2 type I ATP competitor inhibitors with a linker and pomalidomide or thalidomide known to mediate PROTAC-based degradation. The structures established that the C2 carbon of the pyrimidine ring present in both inhibitors is solvent exposed allowing attachment of the linker without impairing kinase binding. Furthermore, 2 N atoms of the pyrimidine ring mediate hydrogen bonding interactions with the L932 and E930 residues, in the hinge between the N- and the C-terminal lobes of JAK2 kinase domain. Specificity, degradation of target molecules, and efficacy were assessed in vitro in cell lines and in patient-derived xenografts of Ph-like ALL cells and in an in vivo model using Ph-like ALL cells from a CRLF2 rearranged and JAK2 nonmutated Ph⁺-ALL patient.