Discovery and Characterization of Novel BLIMP‑1 Heterobifunctional Ligand-Directed Degraders

Discovery and Characterization of Novel BLIMP‑1 Heterobifunctional Ligand-Directed Degraders

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 suppor...

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1. Verfasser: Bryan J. Simmons (22676881) (author)
Weitere Verfasser: Lynda Groocock (18218650) (author), Jesus Moreno (1312926) (author), David S. Peters (9079778) (author), Meredith E. Hughes (8822891) (author), Vijay Veeravalli (17374410) (author), Jennifer M. Crawford (1453204) (author), Matthew Chalkley (22676884) (author), Mark Griffith (22676887) (author), Melissa Plooster (22676890) (author), Bo Hu (126105) (author), Jim Gamez (22384825) (author), Jim Leisten (1562386) (author), Michael J. Barnes (22676893) (author), Jason Chinn (2500474) (author), Gauri Deb (3625370) (author), Hardik Modi (22676896) (author), Madhu Katepalli (22676899) (author), Dahlia Weiss (22384834) (author), Walter Won (22676902) (author), Zhenghang Sun (19474606) (author), Shan Yu (219591) (author), Cameron Reid (22676905) (author), Andrew F. Donnell (1893616) (author), Ling Li (38566) (author), Edmond R. Watson (19198701) (author), Sophie Perrin-Ninkovic (15067518) (author), Lihong Shi (481066) (author), Rama Krishna Narla (1562347) (author), Christoph W. Zapf (2019895) (author), Neil Bence (720479) (author), Antonia Lopez-Girona (8596584) (author), Jennifer R. Riggs (1278165) (author)
Veröffentlicht: 2025
Schlagworte:
Biophysics
Biochemistry
Cell Biology
Genetics
Molecular Biology
Physiology
Pharmacology
Biotechnology
Immunology
Cancer
Hematology
Computational Biology
Biological Sciences not elsewhere classified
Chemical Sciences not elsewhere classified
underlie disease manifestation
tumor cell proliferation
expected antitumor response
elevated metabolic state
vivo mm models
directed degraders b
1 heterobifunctional ligand
directed degrader
activated b
terminal differentiation
multiple myeloma
immunoglobulin production
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Beschreibung
Zusammenfassung: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.

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