ArticleJournal of hematology & oncology2024
Novel potent molecular glue degraders against broad range of hematological cancer cell lines via multiple neosubstrates degradation.
Article in Journal of hematology & oncology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Review
- Mapping the global landscape of molecular glues in drug discovery: a bibliometric analysis from 2010 to 2024.Naunyn-Schmiedeberg's archives of pharmacology · 2026Review
- Exploring Novel E3 Ligases and Neosubstrates for Molecular Glue Degraders and Therapeutic Applications in Cancer.Oncology research · 2026Review
- Integrated analysis of polytranscriptomics reveals TNFSF ligand genes in pancreatic cancer prognosis and immune regulation.BMC immunology · 2025Article
- Photodynamic therapeutic activity of novel porphyrins against lung squamous cell carcinoma.BMC cancer · 2025Article
- Targeting RNA-binding proteins with small molecules: perspectives and challenges.Frontiers in chemistry · 2025Review
- Discovery and Characterization of Novel IKZF1/3 Glue Degraders against Multiple Hematological Cancer Cell Lines.Oncology research · 2025Article
- Prognostic significance of early alpha fetoprotein and des-gamma carboxy prothrombin responses in unresectable hepatocellular carcinoma patients undergoing triple combination therapy.Frontiers in immunology · 2024Article
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Authors and funding
23 authors.
Funding
Abstract
backgroundTargeted protein degradation of neosubstrates plays a crucial role in hematological cancer treatment involving immunomodulatory imide drugs (IMiDs) therapy. Nevertheless, the persistence of inevitable drug resistance and hematological toxicities represents a significant obstacle to their clinical effectiveness.
methodsPhenotypic profiling of a small molecule compounds library in multiple hematological cancer cell lines was conducted to screen for hit degraders. Molecular dynamic-based rational design and cell-based functional assays were conducted to develop more potent degraders. Multiple myeloma (MM) tumor xenograft models were employed to investigate the antitumor efficacy of the degraders as single or combined agents with standard of care agents. Unbiased proteomics was employed to identify multiple therapeutically relevant neosubstrates targeted by the degraders. MM patient-derived cell lines (PDCs) and a panel of solid cancer cell lines were utilized to investigate the effects of candidate degrader on different stage of MM cells and solid malignancies. Unbiased proteomics of IMiDs-resistant MM cells, cell-based functional assays and RT-PCR analysis of clinical MM specimens were utilized to explore the role of BRD9 associated with IMiDs resistance and MM progression.
resultsWe identified a novel cereblon (CRBN)-dependent lead degrader with phthalazinone scaffold, MGD-4, which induced the degradation of Ikaros proteins. We further developed a novel potent candidate, MGD-28, significantly inhibited the growth of hematological cancer cells and induced the degradation of IKZF1/2/3 and CK1α with nanomolar potency via a Cullin-CRBN dependent pathway. Oral administration of MGD-4 and MGD-28 effectively inhibited MM tumor growth and exhibited significant synergistic effects with standard of care agents. MGD-28 exhibited preferentially profound cytotoxicity towards MM PDCs at different disease stages and broad antiproliferative activity in multiple solid malignancies. BRD9 modulated IMiDs resistance, and the expression of BRD9 was significant positively correlated with IKZF1/2/3 and CK1α in MM specimens at different stages. We also observed pronounced synergetic efficacy between the BRD9 inhibitor and MGD-28 for MM treatment.
conclusionsOur findings present a strategy for the multi-targeted degradation of Ikaros proteins and CK1α against hematological cancers, which may be expanded to additional targets and indications. This strategy may enhance efficacy treatment against multiple hematological cancers and solid tumors.
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