PROTAC-mediated NR4A1 degradation as a novel strategy for cancer immunotherapy.

Autor:	Wang L; Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA., Xiao Y; Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA., Luo Y; Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA., Master RP; Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA., Mo J; Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA., Kim MC; Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.; Veterinary Diagnostic Laboratory Medicine, College of Veterinary Medicine, Jeju National University, Jeju-si, South Korea., Liu Y; Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA., Maharjan CK; Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA., Patel UM; Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA., De U; Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA., Carelock ME; Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA., Tithi TI; Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA., Li X; Sanofi Oncology, Sanofi , Cambridge, MA, USA., Shaffer DR; Sanofi Oncology, Sanofi , Cambridge, MA, USA., Guertin KR; Sanofi Integrated Drug Discovery, Sanofi , Cambridge, MA, USA., Zhuang H; Rheumatology and Clinical Immunology, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA., Moser E; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA., Smalley KSM; Department of Tumor Biology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Lv D; Department of Biochemistry and Structural Biology, Center of Innovative Drug Discovery, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA., Zhou D; Department of Biochemistry and Structural Biology, Center of Innovative Drug Discovery, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA., Zheng G; Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA.; University of Florida Health Cancer Center, University of Florida , Gainesville, FL, USA., Zhang W; Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.; University of Florida Health Cancer Center, University of Florida , Gainesville, FL, USA.
Jazyk:	angličtina
Zdroj:	The Journal of experimental medicine [J Exp Med] 2024 Mar 04; Vol. 221 (3). Date of Electronic Publication: 2024 Feb 09.
DOI:	10.1084/jem.20231519
Abstrakt:	An effective cancer therapy requires killing cancer cells and targeting the tumor microenvironment (TME). Searching for molecules critical for multiple cell types in the TME, we identified NR4A1 as one such molecule that can maintain the immune suppressive TME. Here, we establish NR4A1 as a valid target for cancer immunotherapy and describe a first-of-its-kind proteolysis-targeting chimera (PROTAC, named NR-V04) against NR4A1. NR-V04 degrades NR4A1 within hours in vitro and exhibits long-lasting NR4A1 degradation in tumors with an excellent safety profile. NR-V04 inhibits and frequently eradicates established tumors. At the mechanistic level, NR-V04 induces the tumor-infiltrating (TI) B cells and effector memory CD8+ T (Tem) cells and reduces monocytic myeloid-derived suppressor cells (m-MDSC), all of which are known to be clinically relevant immune cell populations in human melanomas. Overall, NR-V04-mediated NR4A1 degradation holds promise for enhancing anticancer immune responses and offers a new avenue for treating various types of cancers such as melanoma. (© 2024 Wang et al.)
Databáze:	MEDLINE
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