P=N/A, N=1, Completed, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine; Shanghai Children's Medical Center, Shanghai Jiao Tong Universit

Cereblon (CRBN) is the target of thalidomide derivatives1 that achieve therapeutic efficacy against some haematologic neoplasias2-4 by recruiting neosubstrates for degradation5-7...Structural investigations provide a mechanistic basis for the effects of the allosteric ligand by shifting the conformational distribution of CRBNopen to a novel CRBNint and increasing the CRBNclosed state. The discovery of a cryptic allosteric binding site on CRBN that alters the functional effects of orthosteric ligands opens new directions with broad implications for improving the selectivity and efficacy of CRBN therapeutics.

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...Methyl ester analogs of these compounds led to substantial proteasomal degradation of the TEAD•YAP/TAZ complex in cancer cells. This work provides a strategy for depletion of nuclear YAP and TAZ and for exploration of their TEAD-dependent and TEAD-independent activities in vivo .

P=N/A, N=545, Completed, Shanghai Zhongshan Hospital

P2, N=45, Not yet recruiting, Medicines Development for Global Health | Initiation date: Oct 2025 --> Jan 2026

MINDFuL is a proof-of-concept study evaluating the efficacy and safety of XPro1595 (1.0 mg/kg/wk) in patients with early AD and biomarkers of inflammation. Detailed results of unblinded cognitive, functional, safety, and biomarker data will be presented.

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.