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 bet...
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Veröffentlicht in: | Scientific reports 2019-07, Vol.9 (1), p.10811-9, Article 10811 |
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Sprache: | eng |
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Zusammenfassung: | 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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ISSN: | 2045-2322 2045-2322 |
DOI: | 10.1038/s41598-019-46948-5 |