This system is self-assembled from a pentavalent arsenate prodrug (AsO₄³⁻), the hydrogen sulfide (H₂S) donor GYY4137, and the lactate export inhibitor diclofenac (DCF), enabling precise responsiveness to the acidic and reductive tumor microenvironment...This is evidenced by the release of damage-associated molecular patterns (DAMPs), dendritic cell maturation, and T cell activation. By integrating lactate metabolism regulation, prodrug activation, and immune remodeling, this strategy provides a promising avenue for combined chemo-immunotherapy of HCC.

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.

Transcriptomic analysis revealed that XPro1595 in females with PNI upregulated mitochondrial, myelination, motor function, and immune regulation gene pathways while it downregulated inflammatory, extracellular matrix, and tumor progression pathways. Overall, we demonstrated that XPro1595 exhibited antitumor, neuroprotective, and analgesic properties in female mice, likely by promoting neuronal regeneration and mitochondrial function, while reducing inflammation and extracellular remodeling.

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.

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.

Discontinuation of maintenance TNFi resulted in higher rates of relapse of RA than continuation.

Therapeutically, slow-release donors (SG1002, GYY4137), mitochondria-targeted vectors (AP39), photo- or thiol-activated "smart" scaffolds, diet-derived polysulfides/isothiocyanates and microbiota engineering aim to restore the protective RSS window. Key challenges are a narrow therapeutic margin and real-time quantification of persulfide fluxes. Harnessing RSS therefore offers a route to rebalance redox homeostasis across diverse chronic diseases.

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.