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].
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