We previously reported a significant correlation between protein-protein hydrogen bond robustness and the stability of the CRBN-CK1α complex induced by the antimyeloma drug lenalidomide. In this work, we demonstrate that this relationship is not unique for that system but rather represents a reproducible physicochemical phenomenon underlying the mechanism of action of chemically diverse MGs, including additional IMiDs and Fusicoccin A. Our results shed light on a vaguely understood phenomenon and pave the way for the development of new computational methods that enable the rational discovery of molecular glues.
Our results show that leptin levels are increased (independently of body mass index) in patients with DLBCL belonging to the R2-GDP-GOTEL phase II clinical trial, and these elevated levels are associated with a worse response to treatment and survival using lenalidomide as immunomodulator...Taken together, these data indicate that leptin could be a promising and predictive response biomarker of treatment efficacy in patients with lymphoma. Our findings on leptin in patients with R/R DLBCL could also arouse great interest given its potential applications as a target of treatment.
This study provides compelling evidence demonstrating that C4 is a highly promising anticancer compound. It also provides important evidence for the development of novel nucleic acid aptamer-PROTAC conjugate drugs for more clinical applications.
These patients show a good prognosis and respond to treatment with lenalidomide, but some cases progress to acute myeloid leukemia...In other MDS patients, del(5q) is combined with other chromosomal abnormalities, giving rise to a condition of complex karyotype, associated with frequent TP53 mutations and with a poor prognosis. Two different molecular pathways seem to be responsible for the generation of MDS with isolated del(5q) or of MDS with del(5q) associated with a complex karyotype.
The patient was treated with a bortezomib-based regimen including bortezomib, lenalidomide, and dexamethasone, along with supportive therapy including bisphosphonates and thromboprophylaxis. This case highlights the diagnostic complexity of IgM MM and emphasizes the importance of comprehensive evaluation, including bone marrow examination, advanced imaging, and detailed protein studies for accurate differentiation from other IgM-producing disorders. Early recognition and appropriate treatment with novel agents may improve outcomes in this rare myeloma variant.
Immunomodulatory drugs (IMiDs) like lenalidomide and pomalidomide degrade IKZF1/3 and are combined with other therapies to treat hematologic malignancies, including multiple myeloma and non-Hodgkin lymphoma. Molecular docking studies suggested that DIX-01 may form stable ternary complexes with CRBN-IKZF1 and CRBN-GSPT1, providing a structural basis for its dual-target degradation activity. Furthermore, DIX-01 significantly inhibited tumor growth in a zebrafish xenograft model transplanted with human acute myeloid leukemia cells (MV4-11), supporting its potential as a therapeutic agent for hematologic malignancies.
2 months ago
Journal
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IKZF1 (IKAROS Family Zinc Finger 1) • CRBN (Cereblon) • GSPT1 (G1 To S Phase Transition 1)
Although lenalidomide/bortezomib/dexamethasone (RVd) and cyclophosphamide/bortezomib/dexamethasone (CyBorD) are clinically effective, their precise impacts on PC/B-cell maturation remain unclear. RVd responders further downregulated CD56, CD269, and CD329, and increased CD243. These shared and divergent modulations elucidate the molecular underpinnings of RVd and CyBorD efficacy and inform precision regimen selection.
New therapeutic options to reduce the red blood cell (RBC) transfusion burden have emerged since 2020 and include luspatercept and imetelstat. Erythropoiesis-stimulating agents and lenalidomide also address anemia and are generally recommended to start at the time of transfusion dependency, although emerging data suggest that an earlier start of these interventions might offer clinical benefits...Targeted therapy directed to the presence of an IDH1 mutation is U.S. Food and Drug Administration (FDA) approved for the rare IDH1 mutated MDS (<10% of the time) and consideration to use an IDH2 inhibitor for IDH2 mutated MDS (<5% of the time) is reasonable. Interestingly, IDH mutations seem to appear with increased frequency in older patients and in patients with underlying autoimmune/rheumatological disorders.1.