The PROTAC designed by Dobrovolsky et al leads to the triple degradation of BTK, IKZF1, and IKZF3 through their Ub and consequent degradation by the proteasome. This small molecule degrades both WT and C481S-mutated BTK proteins and overcomes ibrutinib resistance in B-cell malignancies in vivo. CRBN, cereblon; PDX, patient-derived xenograft; Ub, ubiquitination; WT, wild-type. Professional illustration by Somersault18:24.