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TitleDiscovery and Characterization of Novel BLIMP-1 Heterobifunctional Ligand-Directed Degraders.
Journal, issue, pagesJ Med Chem, Vol. 68, Issue 23, Page 25385-25402, Year 2025
Publish dateDec 11, 2025
AuthorsBryan J Simmons / Lynda Groocock / Jesus Moreno / David S Peters / Meredith E Hughes / Vijay Veeravalli / Jennifer M Crawford / Matthew Chalkley / Mark Griffith / Melissa Plooster / Bo Hu / Jim Gamez / Jim Leisten / Michael J Barnes / Jason Chinn / Gauri Deb / Hardik Modi / Madhu Katepalli / Dahlia Weiss / Walter Won / Zhenghang Sun / Shan Yu / Cameron Reid / Andrew F Donnell / Ling Li / Edmond R Watson / Sophie Perrin-Ninkovic / Lihong Shi / Rama Krishna Narla / Christoph W Zapf / Neil Bence / Antonia Lopez-Girona / Jennifer R Riggs /
PubMed AbstractB-lymphocyte-induced maturation protein 1 (BLIMP-1/PRDM1) is a master transcriptional repressor essential for terminal differentiation of activated B-cells into bone-marrow resident plasma cells. ...B-lymphocyte-induced maturation protein 1 (BLIMP-1/PRDM1) is a master transcriptional repressor essential for terminal differentiation of activated B-cells into bone-marrow resident plasma cells. Multiple myeloma (MM) is a plasma cell malignancy wherein the BLIMP-1 regulon remains critical to support basal cell functions, such as an elevated metabolic state and immunoglobulin production that underlie disease manifestation and tumor cell proliferation. It is predicted that perturbation of BLIMP-1 will significantly impact tumor cell homeostasis and ultimately reduce MM cell survival. Herein, we describe the discovery and optimization of the first orally bioavailable BLIMP-1 heterobifunctional ligand-directed degrader (LDD) and demonstration of the expected antitumor response and immunomodulatory biology following BLIMP-1 degradation using preclinical in vivo MM models.
External linksJ Med Chem / PubMed:41284831
MethodsEM (single particle) / X-ray diffraction
Resolution3.2 - 3.703 Å
Structure data

72178

9q33

EMDB-72178, PDB-9q33:
Cereblon Ternary Complex with Blimp1 and compound 5
Method: EM (single particle) / Resolution: 3.2 Å

PDB-9q1g:
Blimp-1 with compound 5
Method: X-RAY DIFFRACTION / Resolution: 3.703 Å

Chemicals

PDB-1cnq:
FRUCTOSE-1,6-BISPHOSPHATASE COMPLEXED WITH FRUCTOSE-6-PHOSPHATE AND ZINC IONS

ChemComp-ZN:
Unknown entry

PDB-1cn1:
CRYSTAL STRUCTURE OF DEMETALLIZED CONCANAVALIN A. THE METAL-BINDING REGION

Source
  • homo sapiens (human)
KeywordsTRANSCRIPTION / factor / B-cell / lymphocyte / LIGASE / Liganded Cereblon Ligase Substrate

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