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.

P2, N=120, Active, not recruiting, Johns Hopkins University | Recruiting --> Active, not recruiting

P1, N=9, Active, not recruiting, NYU Langone Health | Recruiting --> Active, not recruiting | Trial completion date: Jan 2026 --> Jul 2026

Further anti-cytokine therapies include tocilizumab (anti-interleukin-6) for juvenile systemic sclerosis-associated interstitial lung disease, anti-interleukin-1β/18 combinations (MAS-825), and anti-tumour necrosis factor-alpha. Understanding disease-specific pathophysiology-from interferon activity assessment to genomic sequencing-is essential for optimal therapeutic targeting. Multicentre collaborations are needed to evaluate long-term efficacy and safety of these targeted interventions.

These compounds incorporated the natural product CGA as the target-binding ligand, conjugated to pomalidomide (an E3 ligase-recruiting moiety) via various synthetic linkers. This study successfully applied an effective strategy for target identification and medication discovery of natural compounds. In addition, CGA-PROTAC A7 was synthesized in one step with an overall yield of 45.96%, providing a feasible route for synthesis and establishing a basis for the combination of natural product polyphenols with PROTAC technology.

P2, N=180, Recruiting, AbbVie

The brain-penetrant drug ibudilast, which prevents the binding of MIF to CD74, decreased brain metastasis in experimental models in vivo and in patient-derived organotypic cultures ex vivo in a primary tumor-agnostic manner. These findings suggest that MIF/CD74-induced reprogramming of myeloid cells in brain disorders is a vulnerability that could be exploited therapeutically against brain metastases, and possibly other brain disorders.

Immunomodulatory imide drugs (IMiDs) like lenalidomide and pomalidomide are effective in treating multiple myeloma (MM) but pose hematotoxicity risks by degrading neosubstrates Ikaros (IKZF1) and Aiolos (IKZF3). Moreover, we have identified a CRBN ligand that mitigates these safety liabilities and can be effectively incorporated into PROTACs. This advancement provides a promising path toward safer preclinical development of PROTACs, especially as the field expands into chronic disease treatments beyond oncology.

Four LJH685-based PROTACs, composed of pomalidomide (a cereblon E3 ligase ligand) and different lengths of polyethylene glycol (PEG) linkers, decreased both total RSK2 and phosphorylated RSK2Ser227 levels in HMCLs...These results emphasize the critical role of linker length in optimizing PROTAC efficacy for targeting RSK2. Future exploration of diverse E3 ligases could enable optimization of PROTAC selectivity.

P2, N=250, Active, not recruiting, Avalo Therapeutics, Inc. | Recruiting --> Active, not recruiting

The present review integrates pharmacological, toxicological, and formulation-focused evidence to provide a unified assessment of emodin and the anthraquinone scaffold. Particular emphasis is placed on bidirectional, dose- and context-dependent effects on the liver and kidney; the modulation of cytochrome P450 enzymes, UGTs, and transporters; and emerging preclinical formulation strategies that aim to decouple intrinsic bioactivity from pharmacokinetic limitations.

P2, N=156, Not yet recruiting, Curacle Co., Ltd.