NOTCH plays a pivotal role during normal development as well as in hereditary disorders and cancer. γ-secretase inhibitors are generally accustomed to probe NOTCH function, but additionally block processing of several other proteins. We discovered a brand new type of small molecule inhibitor that disrupts the interaction between NOTCH and RBPJ, the primary transcriptional effector of NOTCH signaling. RBPJ Inhibitor-1 (RIN1) also blocked the running interaction of RBPJ with SHARP, a scaffold protein that forms a transcriptional repressor complex with RBPJ even without the NOTCH signaling. RIN1 caused alterations in gene expression that was similar to siRNA silencing of RBPJ instead of inhibition at the amount of NOTCH itself. In line with disruption of NOTCH signaling, RIN1 inhibited the proliferation of hematologic cancer cell lines and promoted skeletal muscle differentiation from C2C12 myoblasts. Thus, RIN1 inhibits RBPJ in the repressing and activating contexts, and could be exploited for chemical biology and therapeutic applications.

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