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Disruption of NOTCH signaling by a small molecule inhibitor of the transcription factor RBPJ

NOTCH plays a pivotal role during normal development and in congenital disorders and cancer. γ-secretase inhibitors are commonly used to probe NOTCH function, but also block processing of numerous other proteins. 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 that resembled siRNA silencing of RBPJ rather than inhibition at the level of NOTCH itself. Consistent 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 its repressing and activating contexts, and can be exploited for chemical biology and therapeutic applications.

 

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This passage describes the discovery of a new class of small molecule inhibitor, RBPJ Inhibitor-1 (RIN1), which disrupts the interaction between NOTCH and RBPJ, the main transcriptional effector of NOTCH signaling. RIN1 also blocks the functional interaction of RBPJ with SHARP, a scaffold protein that forms a transcriptional repressor complex with RBPJ in the absence of NOTCH signaling. This results in changes in gene expression that resemble siRNA silencing of RBPJ, rather than inhibition at the level of NOTCH itself.

The authors report that RIN1 inhibits the proliferation of hematologic cancer cell lines and promotes skeletal muscle differentiation from C2C12 myoblasts. This suggests that RIN1 can be used for both chemical biology and therapeutic applications.

The discovery of RIN1 is significant because γ-secretase inhibitors, which are commonly used to probe NOTCH function, also block processing of numerous other proteins. RIN1 specifically targets the interaction between NOTCH and RBPJ, which could lead to more specific and targeted therapies for diseases involving NOTCH signaling.

Related Products

Cat.No. Product Name Information
S3376 RIN1 (RBPJ Inhibitor-1) RIN1 (RBPJ Inhibitor-1) is a potent inhibitor of the transcription factor RBPJ that disrupts the interaction between NOTCH and RBPJ.

Related Targets

Notch