P4, N=202, Not yet recruiting, Sint Maartenskliniek Stichting

Clinically validated examples include thalidomide analogs that recruit cereblon (CRBN) to degrade IKAROS family zinc finger 1/3 in multiple myeloma, and arylsulfonamide-based MGDs that promote the degradation of RNA-binding protein 39 in acute myeloid leukemia and solid tumors...By integrating multidisciplinary discovery strategies with translational oncology, the field is moving toward the development of next-generation MGDs with enhanced specificity, broader substrate scope, and improved resistance profiles. This study aims to elucidate how these innovations expand the degradable proteome and establish MGDs as a cornerstone of precision cancer therapy, thereby redefining the boundaries of drug discovery and providing customizable degraders tailored to diverse cancer contexts.

P1/2, N=95, Not yet recruiting, Elevara Medicines Limited

P2, N=45, Recruiting, Medicines Development for Global Health | Not yet recruiting --> Recruiting | Initiation date: Jan 2026 --> May 2026

P1/2, N=24, Not yet recruiting, Elevara Medicines Limited

P3, N=306, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Feb 2026 --> Feb 2027

P2, N=180, Recruiting, Elevara Medicines Limited | Not yet recruiting --> Recruiting

P=N/A, N=50, Affiliated Hospital of North Sichuan Medical College; Affiliated Hospital of North Sichuan Medical College

Febuxostat is a selective XOD inhibitor, designed to target XOD, and thalidomide functions as a ligand for the Cereblon (CRBN) E3 ubiquitin ligase. Furthermore, the DeXOD can ameliorate glomerular capsular dilatation and renal tubular epithelial damage, while demonstrating no observable hepatotoxic effects. This strategy effectively circumvents the therapeutic limitations of conventional xanthine oxidase inhibitors, thereby offering a promising therapeutic paradigm for hyperuricemia and its complications.

We design and synthesize heterobifunctional molecules that consist of flufenamic acid analogs that bind to the allosteric TEAD lipid pocket, a long and flexible linker, and thalidomide to engage E3 ubiquitin ligase component cereblon. Proteasomal degradation of TEAD, YAP, and TAZ for the carboxylic acid compounds was modest, but methyl ester analogs led to substantial degradation of these proteins in cancer cells. This work provides a strategy for depletion of YAP and TAZ and for exploration of their TEAD-dependent and TEAD-independent activities in vivo.

P4, N=312, Recruiting, Sixth Affiliated Hospital, Sun Yat-sen University

Beyond protein degradation, the diverse biological activities of thalidomide are discussed, including modulation of cytokines, angiogenesis, and immune signaling pathways. Collectively, thalidomide exemplifies how mechanistic insight, synthetic innovation and careful risk-benefit evaluation can transform a once-discarded molecule into a cornerstone of contemporary drug design.