The success of thalidomide working as a molecular glue proves the concept of E3 ligase based targeted protein degradation as an effective therapeutic strategy, thus giving confidence to expand the discovery of new molecular glues, E3 ligases and their neosubstrate targets. Efforts to develop rational strategies for discovering new molecular glue degraders and widen the bottleneck of serendipitous discovery has led to the emergence of several successful approaches relying on high throughput chemical library screenings. One such strategy successfully identified four new molecular glue degraders, dCeMM 1/2/3/4, by screening a library of 2,000 cytotoxic/cytostatic small molecules for compounds with E3 dependent antiproliferative activity. As shown in Supplemental Information Table , dCeMM1 shares a similar arylsulfonamide structure and activity as other RBM39 degraders such as Indisulam, recruiting RBM39 to the DCAF15 subunit of CRL DCAF15 . dCeMM 2/3/4 are cyclin K degraders that stabilize cyclin-dependent kinase 12 (CDK12)-cyclin K binding to DDB1CUL4B E3 at the CDK12-DDB1 interface. While dCeMM2/3 are structurally novel and similar to each other, dCeMM4 shares similarity with other cyclin K degraders such as Glue01 (Supplemental Information Table ). In another rational discovery approach, a library of 350,000 chemical compounds was screened using a fluorescence polarization-based binding assay, to detect substances that enhance the PPI of the oncogenic transcription factor β-Catenin, and its E3 ligase, SCFβ-TrCP. Two lead compounds NRX-252114 and NRX-252262 (Supplemental Information Table ) were designed using SBDD from four initially identified first generation compounds with a conserved 6trifluoromethylpyridone bound to a biaryl amide chemical scaffold. In another approach, database mining was used to screen for correlations between the cytotoxicity of a 4,518 small molecule chemical library and the mRNA levels of 499 E3 ligase components against 518 human cancer cell lines. This strategy led to the discovery of compound CR8 (Supplemental Information Table ) which depletes cyclin K by acting as a molecular glue stabilizing the CDK12-cyclin K and DDB1 complex. Advances made using structure-based drug optimization to develop thalidomide based analogs with reduced teratogenicity , enhanced potency, and better target specificity have led to the successful development of promising new therapeutics currently ranging from the preclinical stage to the Phase II clinical stage: CC-122 , CC-220 , CC90009 , CC-92480 , ZXH-1-161 , and SJ6986 66 (Supplemental Information Table ). A structure similarity analysis of the CAS patent database for compounds with 90% similarity to thalidomide using ChemScape software within SciFinder n 73 (Supplemental Information Figure ) shows significant numbers of recent patents related to thalidomide-based analogs, Of these 219 compounds identified, the top 8 compounds with the most frequent patent associations all retain the essential glutarimide moiety which is necessary for CRBN E3 ligase binding. Substitutions on the C4-6 positions of phthaloyl ring and variation of the C3 carbonyl influence neosubstrate binding specificity and degradation potency. These ChemScape results highlight the research interest and relevance of thalidomide analog drugs.