thalidomide

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.

While first-generation TRK kinase inhibitors, such as entrectinib and larotrectinib, have shown positive responses in TRK fusion-positive cancers, resistance mutations against these inhibitors in the kinase domain limit their efficacy...By conjugating entrectinib to thalidomide, we identified JWJ-01-378 as a potent and selective cereblon (CRBN)-recruiting degrader of the TPM3-TRKA fusion...TPM3-TRKA degradation by JWJ-01-378 suppressed downstream signaling and reduced cancer cell viability, with improved responses compared to a heterobifunctional control compound that cannot degrade TPM3-TRKA. Together, our study expands the toolbox of selective compounds for evaluating targeted degradation of TRK fusions in diseases including cancer.

Early intervention with daratumumab may reduce the risk of disease progression and mortality in people with high-risk SMM. The evidence on the risk of adverse events with daratumumab is very uncertain. For immunomodulatory agents, the available evidence is of very low certainty, partly due to conflicting results, so we are unable to draw conclusions about their effects. There is insufficient evidence to support the use of older agents like alkylating agents or cytokine inhibitors. The decision to initiate early treatment in high-risk SMM requires a careful, individualized risk-benefit assessment and shared decision-making.

P3, N=138, Completed, Air Force Military Medical University, China | Recruiting --> Completed

We discuss clinical evidence, limitations, and practical considerations for sirolimus, PI3K inhibitors, thalidomide, MEK inhibitors, and KRAS-directed agents, as well as emerging combination and intermittent strategies to balance efficacy and toxicity...Targeted therapies are shifting management from procedure-centered to biology-guided care. Future progress depends on standardized molecular testing, patient-centered outcomes, and optimized treatment duration to achieve durable disease control with acceptable long-term toxicity.

P2, N=30, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Feb 2026 --> Feb 2027 | Trial primary completion date: Feb 2026 --> Feb 2027

Mechanistically, the CRL4ACRBN E3 complex ubiquitinates KEAP1 at K84 and K312, driving KEAP1 degradation. CRBN inhibitor thalidomide and IKE combination treatment results in markedly retarded tumor progression. Our study reveals a crucial pro-ferroptotic role for TrxR1 and nominates it as a potential biomarker for guiding future ferroptosis-inducing therapies in select cancers.

P2, N=232, Recruiting, Medical University of Vienna | N=100 --> 232

P4, N=55, Completed, Institute of Hematology & Blood Diseases Hospital, China | Unknown status --> Completed

P4, N=44, Completed, Institute of Hematology & Blood Diseases Hospital, China | Unknown status --> Completed

P3, N=177, Active, not recruiting, University of Arkansas | Trial completion date: Aug 2026 --> Aug 2027 | Trial primary completion date: Aug 2026 --> Aug 2027

P3, N=300, Active, not recruiting, Australasian Leukaemia and Lymphoma Group (ALLG) | Recruiting --> Active, not recruiting