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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Autor principal:	Bryan J. Simmons (22676881) (author)
Altres autors:	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)
Publicat:	2025
Matèries:	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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author	Bryan J. Simmons (22676881)
author2	Lynda Groocock (18218650) Jesus Moreno (1312926) David S. Peters (9079778) Meredith E. Hughes (8822891) Vijay Veeravalli (17374410) Jennifer M. Crawford (1453204) Matthew Chalkley (22676884) Mark Griffith (22676887) Melissa Plooster (22676890) Bo Hu (126105) Jim Gamez (22384825) Jim Leisten (1562386) Michael J. Barnes (22676893) Jason Chinn (2500474) Gauri Deb (3625370) Hardik Modi (22676896) Madhu Katepalli (22676899) Dahlia Weiss (22384834) Walter Won (22676902) Zhenghang Sun (19474606) Shan Yu (219591) Cameron Reid (22676905) Andrew F. Donnell (1893616) Ling Li (38566) Edmond R. Watson (19198701) Sophie Perrin-Ninkovic (15067518) Lihong Shi (481066) Rama Krishna Narla (1562347) Christoph W. Zapf (2019895) Neil Bence (720479) Antonia Lopez-Girona (8596584) Jennifer R. Riggs (1278165)
author2_role	author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author
author_facet	Bryan J. Simmons (22676881) Lynda Groocock (18218650) Jesus Moreno (1312926) David S. Peters (9079778) Meredith E. Hughes (8822891) Vijay Veeravalli (17374410) Jennifer M. Crawford (1453204) Matthew Chalkley (22676884) Mark Griffith (22676887) Melissa Plooster (22676890) Bo Hu (126105) Jim Gamez (22384825) Jim Leisten (1562386) Michael J. Barnes (22676893) Jason Chinn (2500474) Gauri Deb (3625370) Hardik Modi (22676896) Madhu Katepalli (22676899) Dahlia Weiss (22384834) Walter Won (22676902) Zhenghang Sun (19474606) Shan Yu (219591) Cameron Reid (22676905) Andrew F. Donnell (1893616) Ling Li (38566) Edmond R. Watson (19198701) Sophie Perrin-Ninkovic (15067518) Lihong Shi (481066) Rama Krishna Narla (1562347) Christoph W. Zapf (2019895) Neil Bence (720479) Antonia Lopez-Girona (8596584) Jennifer R. Riggs (1278165)
author_role	author
dc.creator.none.fl_str_mv	Bryan J. Simmons (22676881) Lynda Groocock (18218650) Jesus Moreno (1312926) David S. Peters (9079778) Meredith E. Hughes (8822891) Vijay Veeravalli (17374410) Jennifer M. Crawford (1453204) Matthew Chalkley (22676884) Mark Griffith (22676887) Melissa Plooster (22676890) Bo Hu (126105) Jim Gamez (22384825) Jim Leisten (1562386) Michael J. Barnes (22676893) Jason Chinn (2500474) Gauri Deb (3625370) Hardik Modi (22676896) Madhu Katepalli (22676899) Dahlia Weiss (22384834) Walter Won (22676902) Zhenghang Sun (19474606) Shan Yu (219591) Cameron Reid (22676905) Andrew F. Donnell (1893616) Ling Li (38566) Edmond R. Watson (19198701) Sophie Perrin-Ninkovic (15067518) Lihong Shi (481066) Rama Krishna Narla (1562347) Christoph W. Zapf (2019895) Neil Bence (720479) Antonia Lopez-Girona (8596584) Jennifer R. Riggs (1278165)
dc.date.none.fl_str_mv	2025-11-24T20:08:05Z
dc.identifier.none.fl_str_mv	10.1021/acs.jmedchem.5c02363.s002
dc.relation.none.fl_str_mv	https://figshare.com/articles/dataset/Discovery_and_Characterization_of_Novel_BLIMP_1_Heterobifunctional_Ligand-Directed_Degraders/30698290
dc.rights.none.fl_str_mv	CC BY-NC 4.0 info:eu-repo/semantics/openAccess
dc.subject.none.fl_str_mv	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
dc.title.none.fl_str_mv	Discovery and Characterization of Novel BLIMP‑1 Heterobifunctional Ligand-Directed Degraders
dc.type.none.fl_str_mv	Dataset info:eu-repo/semantics/publishedVersion dataset
description	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.
eu_rights_str_mv	openAccess
id	Manara_27fa1224764b4880da4d2471c2b11c79
identifier_str_mv	10.1021/acs.jmedchem.5c02363.s002
network_acronym_str	Manara
network_name_str	ManaraRepo
oai_identifier_str	oai:figshare.com:article/30698290
publishDate	2025
repository.mail.fl_str_mv
repository.name.fl_str_mv
repository_id_str
rights_invalid_str_mv	CC BY-NC 4.0
spelling	Discovery and Characterization of Novel BLIMP‑1 Heterobifunctional Ligand-Directed DegradersBryan J. Simmons (22676881)Lynda Groocock (18218650)Jesus Moreno (1312926)David S. Peters (9079778)Meredith E. Hughes (8822891)Vijay Veeravalli (17374410)Jennifer M. Crawford (1453204)Matthew Chalkley (22676884)Mark Griffith (22676887)Melissa Plooster (22676890)Bo Hu (126105)Jim Gamez (22384825)Jim Leisten (1562386)Michael J. Barnes (22676893)Jason Chinn (2500474)Gauri Deb (3625370)Hardik Modi (22676896)Madhu Katepalli (22676899)Dahlia Weiss (22384834)Walter Won (22676902)Zhenghang Sun (19474606)Shan Yu (219591)Cameron Reid (22676905)Andrew F. Donnell (1893616)Ling Li (38566)Edmond R. Watson (19198701)Sophie Perrin-Ninkovic (15067518)Lihong Shi (481066)Rama Krishna Narla (1562347)Christoph W. Zapf (2019895)Neil Bence (720479)Antonia Lopez-Girona (8596584)Jennifer R. Riggs (1278165)BiophysicsBiochemistryCell BiologyGeneticsMolecular BiologyPhysiologyPharmacologyBiotechnologyImmunologyCancerHematologyComputational BiologyBiological Sciences not elsewhere classifiedChemical Sciences not elsewhere classifiedunderlie disease manifestationtumor cell proliferationexpected antitumor responseelevated metabolic statevivo mm modelsdirected degraders b1 heterobifunctional liganddirected degraderactivated bterminal differentiationmultiple myelomaimmunoglobulin productionB-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.2025-11-24T20:08:05ZDatasetinfo:eu-repo/semantics/publishedVersiondataset10.1021/acs.jmedchem.5c02363.s002https://figshare.com/articles/dataset/Discovery_and_Characterization_of_Novel_BLIMP_1_Heterobifunctional_Ligand-Directed_Degraders/30698290CC BY-NC 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/306982902025-11-24T20:08:05Z
spellingShingle	Discovery and Characterization of Novel BLIMP‑1 Heterobifunctional Ligand-Directed Degraders Bryan J. Simmons (22676881) 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
status_str	publishedVersion
title	Discovery and Characterization of Novel BLIMP‑1 Heterobifunctional Ligand-Directed Degraders
title_full	Discovery and Characterization of Novel BLIMP‑1 Heterobifunctional Ligand-Directed Degraders
title_fullStr	Discovery and Characterization of Novel BLIMP‑1 Heterobifunctional Ligand-Directed Degraders
title_full_unstemmed	Discovery and Characterization of Novel BLIMP‑1 Heterobifunctional Ligand-Directed Degraders
title_short	Discovery and Characterization of Novel BLIMP‑1 Heterobifunctional Ligand-Directed Degraders
title_sort	Discovery and Characterization of Novel BLIMP‑1 Heterobifunctional Ligand-Directed Degraders
topic	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

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

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