Immunoprecipitation assays and immunoblotting assays show that CC-885 promotes the binding of CRBN to a novel substrate, GSPT1, targeting its degradation. Concerns about the poor toxicity profile of CC-885 led BMS/Celgene to further explore the development of analogs of CC-885 with better antiproliferative activity against a broad panel of AML cell lines. Using CC-885 as a structural template, SAR studies defined a scaffold with a difluoro acetamide linker that maintained a good in vitro selectivity index. From this scaffold, a focused library of a series of difluoro acetamide analogs was synthesized and screened leading to the identification of BMS/Celgene's third generation lead compound CC-90009. Validation studies further demonstrated that CC-90009 shows strong potency and specificity in degrading GSPT1, not IKZF1 or IKZF3. Similar approach was used to explore rationally designed molecular glue degraders showing specificity for IKZF1/3 with higher potency and more rapid degradation profiles than lenalidomide in the treatment of relapsed or refractory multiple myeloma (RRMM). These studies led to the successful identification of an additional 3 rd generation molecular glue degrader, CC-92480 (Supplemental Information Table ). By screening the CRBN modulator library for selective antiproliferative activity in a lenalidomide resistant MM cell line, lead compound 13 was identified and its chemical structure was used as the foundation for SAR studies, distinguishing the minimal pharmacophore necessary to maintain strong antiproliferative activity and rapid IKZF3 degradation. The defined scaffold retains the essential features of the glutarimide ring for binding CRBN, an isoindoline ring similar to lenalidomide with a 4-oxy substitution in place of the 4-amine, and S-chirality while allowing variability on the terminal arylpiperazine. The inspection of a series of arylpiperazine analogs identified CC-92480 as a lead compound for clinical development with reduced off target binding compared to compound 13, specific IKZF1 and IKZF3 degradation, and more potent and rapid degradation profiles than lenalidomide or pomalidomide. Further, additional CELMoDs were identified by screening a focused combinatorial library of 51 compounds with three lenalidomide heterocyclic scaffolds for CRBN dependent antiproliferative activity in a MM cell line. Expression proteomic validation studies of compounds of interest confirmed target specificity. Lead compound ZXH-1-161 was identified, with antiproliferative activity in a MM cell line and improved selectivity for GSPT1 degradation compared to CC-885. Nishiguchi et al. recently explored rational design of novel CRBN dependent molecular glue degraders by screening a chemical library constructed using the essential thalidomide pharmacophore defined from crystallization and SAR studies of IMiDs. A 415-compound focused chemical library was synthesized from 30 thalidomide analog scaffolds and both the landscape of the library by in silico molecular docking analysis and the physiochemical descriptors of included analogs were evaluated prior to phenotypic screening. Lead CELMoD compound SJ6986 was identified with antiproliferative activity against a broad range of cell lines, potent degradation of GSPT1/2 with selectivity over IKZF1/3 and high bioavailablility in mice. This success validates the application of chemical docking strategies to confirm spatial diversity within the binding cavity and calculation of physicochemical descriptors to ensure analogs lie within a drug-like property space, prior to focused combinatorial library synthesis and screening for activity.