thalidomide

P2, N=26, Completed, AIDS Malignancy Consortium | Trial completion date: Jan 2026 --> Apr 2025 | Active, not recruiting --> Completed

During maintenance therapy with sorafenib combined with ITI, median relapse-free survival (mRFS) was also not reached, with 12- and 24-month RFS rates of 73.7% (14/19) and 57.9% (11/19), respectively. The sorafenib combined with ITI regimen is an effective maintenance therapy for FLT3-ITD (+) AML, significantly reducing relapse risk and prolonging survival.

In the present study, we established a modular synthetic platform to systematically generate a set of PROTAC degrader candidates consisting of the CK1δ-specific inhibitor scaffold, alkyl and PEG linker motifs with various lengths, and Cereblon (CRBN)-engaging pomalidomide and thalidomide derivatives as E3 ligase binders. The most potent PROTAC P1d inhibits the phosphorylation of downstream substrates through CK1δ/ε degradation. We establish the requirement of CUL4ACRBN and the proteasome for the P1d-mediated degradation of CK1δ/ε.

Treatment regimens comprised lenalidomide (n = 36) or thalidomide (n = 15) with daratumumab, and pomalidomide (n = 2) with isatuximab. Most patients (n = 38) received frontline therapy, and all were given thromboprophylaxis according to guidelines, mainly aspirin (73%)...Given the limited number of patients and thrombotic events, and the cytokine data available for only two VTE cases, these associations should be regarded as exploratory and interpreted with caution. Overall, these exploratory findings warrant validation in larger, independent cohorts and may help generate hypotheses on how inflammatory signatures influence thrombotic risk and prophylaxis efficacy in MM patients receiving IMiD/anti-CD38-based regimens.

P3, N=452, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2025 --> Oct 2026

Multiple myeloma is a plasma cell malignancy that is susceptible to drugs targeting protein homeostasis such as thalidomide analogues and proteasome inhibitors...As anti-myeloma activity did not associate with dephosphorylation of known DCAF1 kinase substrates, we correlated drug-induced cellular phenotypes with whole-genome CRISPR/Cas9 resistance screening to further define mechanistic activity. These studies identified B32B3 analogues as microtubular destabilising agents with potential DCAF1 kinase independent properties and in vivo efficacy in multiple myeloma and lymphoma.

P2, N=64, Not yet recruiting, Shandong First Medical University Affiliated Cancer Hospital; Shandong First Medical University Affiliated Cancer Hospital

All ligands showed a favorable lipophilicity, and several were able to outperform the binding affinity of thalidomide as a reference...A cellular thermal shift assay further demonstrated that the most potent analogs stabilize CRBN in live cells, confirming their on-target engagement. The development of the series was accompanied by a crystallographic study, which rationalizes the observed improvements in binding affinity and neosubstrate selectivity, and can support further development towards molecular glue activity and PROTACs design.

BETd-246 serves as a tethering agent that links BETi-211 to thalidomide for the development of BET degraders...The effects of BETd-246 were more pronounced than those of JQ1...These findings suggest that TRAT1 plays a crucial role in mediating the effects of BETd-246 in T-ALL. Overall, our results indicate that BETd-246 is a promising therapeutic agent for treating this aggressive form of leukemia.

Compared to gefitinib (IC50 = 4.1 ± 0.01 μM) and thalidomide (IC50 = 13.4 ± 0.5 μM), compounds 6c and 10b exhibited moderate anti-proliferative activity against the MCF-7 breast cancer cell line, with IC50 values of 37.7 ± 3.6 and 31.8 ± 2.0 μM, respectively. In silico studies confirmed that both compounds fit the criteria for orally bioavailable drug candidates, showing high gastrointestinal absorption and no predicted adverse effects on the central nervous system or liver. Additionally, both compounds were predicted to be non-carcinogenic and non-mutagenic.

P2, N=40, Active, not recruiting, Cancer Institute and Hospital, Chinese Academy of Medical Sciences

The model was tested on the anticancer drug (Thalidomide), an antimalarial molecule (Compound 2), and the estrogen receptor modulator (Cyclofenil) to enhance solubility. Additionally, the model was applied to optimize the affinities of molecules targeting Janus kinase 1.