Unleashing the Power of 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 32610, USA., Xiao Y; Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA., Luo Y; Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA.; Current: Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Ole Maaløes Vej 5, Copenhagen N DK-2200, Denmark., Master RP; Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA.; Current: College of Medicine, Florida State University, Tallahassee, FL 32306, USA., Mo J; Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA.; Current: R & D, Thermo Fisher Scientific, Alachua, FL 32615, USA., Kim MC; Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA.; Veterinary Diagnostic Laboratory Medicine, College of Veterinary Medicine, Jeju National University, Jeju-si, Jeju-do, South Korea 63243., Liu Y; Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA., Patel UM; Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA., Li X; Sanofi Oncology, Sanofi, Cambridge, MA 01890., Shaffer D; Sanofi Oncology, Sanofi, Cambridge, MA 01890., Guertin KR; Sanofi Integrated Drug Discovery, Sanofi, Cambridge, MA 01890., Moser E; Division of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, the College of Medicine, University of Florida, Gainesville, FL 32610, USA., Smalley KS; Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA.; Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.; Current: Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Ole Maaløes Vej 5, Copenhagen N DK-2200, Denmark.; Current: College of Medicine, Florida State University, Tallahassee, FL 32306, USA.; Current: R & D, Thermo Fisher Scientific, Alachua, FL 32615, USA.; Veterinary Diagnostic Laboratory Medicine, College of Veterinary Medicine, Jeju National University, Jeju-si, Jeju-do, South Korea 63243.; Sanofi Oncology, Sanofi, Cambridge, MA 01890.; Sanofi Integrated Drug Discovery, Sanofi, Cambridge, MA 01890.; Division of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, the College of Medicine, University of Florida, Gainesville, FL 32610, USA.; Department of Cutaneous Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL 12902.; Department of Biochemistry & Structural Biology, Center of innovative Drug Discovery, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229.; University of Florida Health Cancer Center, University of Florida, Gainesville, FL 32610, USA., Zhou D; Department of Biochemistry & Structural Biology, Center of innovative Drug Discovery, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229., Zheng G; Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.; University of Florida Health Cancer Center, University of Florida, Gainesville, FL 32610, USA., Zhang W; Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA.; University of Florida Health Cancer Center, University of Florida, Gainesville, FL 32610, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Aug 13. Date of Electronic Publication: 2023 Aug 13.
DOI:	10.1101/2023.08.09.552650
Abstrakt:	An effective cancer therapy requires both killing cancer cells and targeting tumor-promoting pathways or cell populations within the tumor microenvironment (TME). We purposely search for molecules that are critical for multiple tumor-promoting cell types and identified nuclear receptor subfamily 4 group A member 1 (NR4A1) as one such molecule. NR4A1 has been shown to promote the aggressiveness of cancer cells and maintain the immune suppressive TME. Using genetic and pharmacological approaches, we establish NR4A1 as a valid therapeutic target for cancer therapy. Importantly, we have developed the first-of-its kind proteolysis-targeting chimera (PROTAC, named NR-V04) against NR4A1. NR-V04 effectively degrades NR4A1 within hours of treatment in vitro and sustains for at least 4 days in vivo , exhibiting long-lasting NR4A1-degradation in tumors and an excellent safety profile. NR-V04 leads to robust tumor inhibition and sometimes eradication of established melanoma tumors. At the mechanistic level, we have identified an unexpected novel mechanism via significant induction of tumor-infiltrating (TI) B cells as well as an inhibition of monocytic myeloid derived suppressor cells (m-MDSC), two clinically relevant immune cell populations in human melanomas. Overall, NR-V04-mediated NR4A1 degradation holds promise for enhancing anti-cancer immune responses and offers a new avenue for treating various types of cancer. Competing Interests: This project was partially supported by an iAward from Sanofi. W.Z., G.Z., D.Z., Y.X., and L.W. hold a patent related to the compound used in this study. X.L., D.S., K.R.G. are Sanofi Employees and holding Sanofi stocks.
Databáze:	MEDLINE
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