NOTCH proteins are trans-membrane receptors that transduce signals from cell-bound JAGGED (JAG) and Delta-like (DLL) families of ligands to mediate cell-cell interactions in processes as diverse as fetal development, heart disease and cancer. NOTCH is cleaved by γ-secretase after activation to release an intracellular domain (NICD) that binds the transcriptional effector RBPJ. RBPJ inhibitor-1 (RIN1) is the first inhibitor of RBPJ which potently disrupts the functional interaction of RBPJ with NOTCH. RIN1 inhibited Hes1-Luciferase, NOTCH3 ICD and RBPJ-VP16-dependent Hes1-Luciferase with IC50s of 0.18, 0.19, and 0.2 µM and Emaxs of 82%, 88% and 81%, respectively. RIN1 (2 µM) decreased RBPJ-VP16-dependent Hes1-Luciferase activity and caused a corresponding decrease in Luciferase reporter mRNA and endogenous RBPJ target gene expression mRNAs. RIN1 decreased cell proliferation in Jurkat, Koptk-1 and Rec-1 cancer cell lines. RIN1 (0.6 µM) decreased the number of MHC+ cells and increased the number of nuclei per cell, indicating that it induced the formation of multinucleated myofibers[2].
RBPJ Inhibitor-1 细胞实验
Cell Line
Concentration
Treated Time
Description
References
C2C12 myoblasts
0.6 µM
4 days
RIN1 promoted the differentiation of C2C12 myoblasts into multinucleated myofibers.
Sci Rep. 2019 Jul 25;9(1):10811.
Jurkat cells
2 µM
8 h
RIN1 suppressed the proliferation of Jurkat cells and induced gene expression changes similar to RBPJ silencing.
Sci Rep. 2019 Jul 25;9(1):10811.
T lymphocytes
2 μM
24 h
To validate the effect of Notch pathway inactivation on Th cell differentiation and apoptosis in patients with uveitis. Results showed that after RIN1 treatment, the expression of Dll4 and RBPJ was significantly reduced, the proportion of Th17/Treg, CD4+/CD8+, and apoptotic cell levels decreased, while mitochondrial membrane potential levels increased.
J Transl Med. 2025 Apr 10;23(1):426.
Peripheral blood CD8+ T cells
10 µM
96 h
To investigate the synergistic regulation of Notch and TGF-β signaling pathways on the differentiation of DP CD8+ TRM cells. Results showed that the addition of DLL4 and TGF-β1 significantly increased CD103 expression, while the addition of RIN1 decreased CD103 expression.
Cell Commun Signal. 2024 Dec 18;22(1):608.
C2C12 myoblasts
0.6 µM
4 days
Promoted muscle cell differentiation into multinucleated myofibers
Sci Rep. 2019 Jul 25;9(1):10811.
Jurkat cells
2 µM
8 h
Compared transcriptomic effects of RIN1, DAPT, and CB-103, RIN1 inhibited cell proliferation
Sci Rep. 2019 Jul 25;9(1):10811.
AD-293 cells
10 µM
17 h
Primary screen for RBPJ inhibitors, RIN1 inhibited UAS-Luc activity
Sci Rep. 2019 Jul 25;9(1):10811.
RBPJ Inhibitor-1 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
BALB/c nude mice
786-O renal cancer cell xenograft model
Intraperitoneal injection
40 mg/kg
Combination of RBPJ inhibitors with CDK4/6 inhibitors showed synergistic effects on renal cancer cells.
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