We discovered a new class of small molecule inhibitor that disrupts the interaction between NOTCH and RBPJ, which is the main transcriptional effector of NOTCH signaling. RBPJ Inhibitor-1 (RIN1) also blocked the functional interaction of RBPJ with SHARP, a scaffold protein that forms a transcriptional repressor complex with RBPJ in the absence of NOTCH signaling. RIN1 induced changes in gene expression resembled siRNA silencing of RBPJ rather than inhibition at the level of NOTCH itself. RIN1 inhibits RBPJ in its repressing and activating contexts. Overall design: Analysis of gene expression on Jurkat cells treated with different inhibitors of the Notch pathway: DAPT (gamma secretase inhibitor), CB-103 (inhibitor works downstream activated receptor but with unknown target), RIN1 (novel inhibitor at the level of RBPJ) and RBPJ siRNA