2. Academic Validation
  3. Disruption of NOTCH signaling by a small molecule inhibitor of the transcription factor RBPJ

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

  • Sci Rep. 2019 Jul 25;9(1):10811. doi: 10.1038/s41598-019-46948-5.
Cecilia Hurtado 1 2,  Alena Safarova 3,  Michael Smith 3,  Raeeun Chung 1,  Arne A N Bruyneel 1,  Jorge Gomez-Galeno 4,  Franz Oswald 5,  Christopher J Larson 2,  John R Cashman 4,  Pilar Ruiz-Lozano 6,  Philip Janiak 7,  Teri Suzuki 3 8,  Mark Mercola 9 10
Affiliations

Affiliations

  • 1 Stanford Cardiovascular Institute and the Department of Medicine, Stanford University, Stanford, CA, 94305, USA.
  • 2 Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
  • 3 Icagen, Oro Valley, AZ, 85755, USA.
  • 4 Human BioMolecular Research Institute, San Diego, CA, 92121, USA.
  • 5 University Medical Center Ulm, 89081, Ulm, Germany.
  • 6 Regencor, Los Altos, CA, 94022, USA.
  • 7 Sanofi, 91380, Chilly-Mazarin, France.
  • 8 Belltree Consulting, L.L.C., Tucson, AZ, 85745, USA.
  • 9 Stanford Cardiovascular Institute and the Department of Medicine, Stanford University, Stanford, CA, 94305, USA. [email protected].
  • 10 Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA. [email protected].
PMID: 31346210 DOI: 10.1038/s41598-019-46948-5
Abstract

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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