P1/2, N=10, Not yet recruiting, M.D. Anderson Cancer Center

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.

P1/2, N=45, Completed, Artiva Biotherapeutics, Inc. | Active, not recruiting --> Completed | Trial primary completion date: Aug 2024 --> Oct 2025

P1, N=100, Recruiting, Zumutor Biologics Inc. | N=33 --> 100

Single-cell analysis of tumor-infiltrating lymphocytes revealed that this combination therapy uniquely expanded tumor-reactive memory-phenotype CD4 and CD8 T cells. Taken together, upon activation by αGalCer/APC, iPSC-iNKT cells are capable of effectively inducing antitumor T cell immunity, making them a promising tool for generating personalized antitumor T cell immunity.

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.

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.

P1/2, N=80, Recruiting, M.D. Anderson Cancer Center | Active, not recruiting --> Recruiting | N=30 --> 80

P1/2, N=9, Terminated, Radboud University Medical Center | N=23 --> 9 | Trial completion date: Sep 2025 --> Jan 2026 | Recruiting --> Terminated | Trial primary completion date: Sep 2025 --> Jan 2026; Stop funding

P2, N=17, Recruiting, Artiva Biotherapeutics, Inc.

P1, N=60, Not yet recruiting, M.D. Anderson Cancer Center