Small molecule-mediated activation of Notch signal transduction.

Authors

Subhamita Dey, Benedetto Daniele Giaimo, Iva Katharina Zöllner, Qingwen Yang, Hina Zarrin, Jasmin Ballout, Martin Diener, Tobias Friedrich, Francesca Ferrante, Jan Dreute, M Lienhard Schmitz, Astrid Weiss, Pierfrancesco Polo, Matthias Lauth, Bernd Gahr, Steffen Just, Marek Bartkuhn, Franz Oswald, Tilman Borggrefe

Published in

Cell death & disease. Jul 02, 2026. Epub Jul 02, 2026.

Abstract

The Notch signaling pathway is pivotal in regulating cell differentiation, stem cell maintenance and oncogenesis. While several Notch inhibitors have been developed, effective small molecule activators are scarce. Here, we identify a small molecule that robustly activates Notch signaling, leading to significant upregulation of Notch target genes in several human cell lines and in Danio rerio embryos. Mechanistically, this compound induces the expression of activated NOTCH3 protein via a cryptic internal promoter within the NOTCH3 locus. Notch induction is markedly diminished upon genetic depletion of NOTCH3 or the canonical Notch transcription factor RBPJ. Furthermore, we demonstrate that the compound inhibits complex I of the respiratory chain. This is accompanied by a raise of cytosolic Ca²⁺ concentration, which is pivotal for the induction of NOTCH3. Functionally, the Notch inducer enforces cell-cycle arrest and promotes terminal differentiation in acute myeloid leukemia (AML) cells. These findings suggest that this small molecule serves as a potent tool for modulating Notch signaling and holds therapeutic potential for Notch-responsive malignancies.

PMID:
42393021
Bibliographic data and abstract were imported from PubMed on 03 Jul 2026.

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