CRBN (Cereblon)

Therapeutic paradigms have shifted from melphalan-based chemotherapy and autologous stem cell transplantation to triplet and quadruplet combinations incorporating immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies, while next-generation immunotherapies, BCMA-directed CAR-T cells, bispecific antibodies, and cereblon E3 ligase modulators, offer unprecedented depth of response. Integrating multi-omics profiling, artificial intelligence (AI)-based analytics, and dynamic biomarkers promises to transform the natural history of these disorders, shifting the trajectory of monoclonal gammopathies from inevitable progression toward durable remission and potential cure. This review delineates the biological continuum underpinning disease progression from MGUS and SMM to MM, and provides a concise overview of recent advances in molecular diagnostics and novel therapeutic strategies within this context.

We also identified dHTC3, a molecular glue that selectively dimerizes BRD4 bromodomain 1 to SCFFBXO3, an E3 ligase not previously accessible for chemical rewiring. Altogether, this study introduces HTC as a facile tool to discover new CIPs and new effectors for proximity pharmacology.

Mechanistically, Tazemetostat appears to reduce IKZF1 binding to the IRF4 promoter and super-enhancer, explaining how the combination with IMiDs/CELMoDs which also have this effect may reach the threshold required to suppress IRF4 expression and ultimately inhibit MM cell growth in resistant cell lines. Our findings highlight a potential strategy for treating MM patients with IMiD resistance.

Oral administration of BMS-986458 results in dose-dependent pharmacokinetics, pharmacodynamics, and significant antitumor efficacy in mouse models of lymphoma. A potential first-in-class agent, BMS-986458, is currently being evaluated in a phase 1/2 clinical trial (NCT06090539) for patients with relapsed/refractory NHL.

The present reactive oxygen species responsive delivery of cytotoxin doxorubicin via a click-to-release reaction between boronate-caged dihydrotetrazines and trans-cyclooctene modified doxorubicin shows excellent chemotherapeutic efficacy and safety in suppressing the growth of some tumors, superior to both direct administration of doxorubicin and reactive oxygen species sensitive prodrug of boronate-caged doxorubicin. We expect this reactive oxygen species responsive bioorthogonal reaction will offer compelling opportunities for precision therapy and provide approaches for studying pathogenesis.

With frontline therapeutic strategies increasingly employing quadruplet induction regimens and prolonged lenalidomide maintenance, resistance to traditional IMiDs has become more prevalent, creating an urgent need for next-generation cereblon E3 ligase modulators (CELMoDs) capable of overcoming IMiD refractoriness and enhancing the immunologic microenvironment. Iberdomide (CC-220) and mezigdomide (CC-92480) are rationally engineered CELMoDs designed to achieve deeper degradation of Ikaros (IKZF1) and Aiolos (IKZF3), restore cereblon-mediated activity, and potentiate immune effector responses...We examine how their pharmacodynamic properties differ from classical IMiDs, their relevance in triple-class and penta-refractory MM, and their integration into emerging combination strategies with monoclonal antibodies and T-cell-redirecting immunotherapies. Special emphasis is placed on ongoing and future trials that may refine their therapeutic positioning, alongside a critical appraisal of the limitations and future directions of this rapidly advancing drug class.

By integrating BRD4 ligands (JQ1, ABBV-075, and HJB97) with strategies like macrocyclization, dual-targeting designs, and the dTAG system, potency and isoform selectivity have been enhanced. The novel mechanism of molecular glue degraders is also explored. Multidimensional optimization is now propelling BRD4-PROTACs towards clinical translation, promising efficient, safe, and precisely controllable new strategies for cancer treatment.

In vivo studies demonstrated a 112% tumor growth inhibition in L858R-induced cancers. These findings suggest that HBE-843 holds promise as a lead compound for developing new drugs to overcome C797S mutant-mediated resistance in clinical settings.

P1, N=27, Recruiting, Abdullah Khan | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2025 --> Dec 2026

Triplet regimens that include an immunomodulatory agent, proteasome inhibitor, and dexamethasone are widely used in newly diagnosed and relapsed/refractory (R/R) multiple myeloma (MM)...Additionally, we have compared these results with similar combinations with the immunomodulatory agent pomalidomide (POM). Our studies indicate that the MEZI/BTZ/DEX triplet is superior to all single agents and POM/BTZ/DEX in terms of potency of antiproliferative and proapoptotic activities, substrate degradation depth and kinetics in the presence of BTZ, and in vivo efficacy. We show that the combination of MEZI with BTZ increases cell death through disruption of multiple phases of the cell cycle and this thereby enhances the direct cytotoxic effects of the combination treatment.

These findings establish XZ739 as a promising therapeutic candidate for BCL-XL-dependent CCA, highlighting its translational potential for rational combination with chemotherapy to overcome resistance while mitigating hematologic toxicity.

To further enhance tumor-specific delivery, we engineered A6@ZIF-8, a pH-sensitive nanocarrier that promotes drug accumulation at tumor sites compared to free A6, leading to improved therapeutic outcomes. Collectively, our data indicate that targeted degradation of eEF2K via PROTAC technology constitutes a novel and therapeutically relevant intervention strategy for TNBC.