Transcription factors IKZF1 and IKZF3 degradation IKZF1 and IKZF3 are lymphocyte lineage transcription factors that are key regulators for the survival of the malignant plasma cells in multiple myeloma. IKZF1 and IKZF3 are considered as undruggable target proteins due to lack of druggable binding pockets. Acting as molecular glue, thalidomide and its analogues, lenalidomide (Revlimid®) and pomalidomide (Pomalyst®) induce formation of a CUL4-DDB1-RBX1-CRBN E3 ligase complex. This ternary complex promotes ubiquitination and degradation of IKZF1 and IKZF3. Degradation of IKZF1 and IKZF3 causes proliferation inhibition of multiple myeloma cells and differentiation suppression of B-cells. These three agents are approved by the U.S. FDA to treat multiple myeloma and del(5q) MDS. Molecular glue compounds CC122, CC220 (iberdomide) and CC-99282 (Table ) degrade IKZF1 and IKZF3 through binding to CRBN E3 ligase. These compounds are currently in Phase I/II clinical trials for treatment of multiple myeloma, non-Hodgkin lymphoma, and systemic lupus erythematosus. CFT7455 (Table ) is a next-generation IKZF1/3 degrader binding to CRBN E3 ligase.