Pharmacological disruption of the Notch transcription factor complex.

Details

Serval ID
serval:BIB_53A51DDF8D0E
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Pharmacological disruption of the Notch transcription factor complex.
Journal
Proceedings of the National Academy of Sciences of the United States of America
Author(s)
Lehal R., Zaric J., Vigolo M., Urech C., Frismantas V., Zangger N., Cao L., Berger A., Chicote I., Loubéry S., Choi S.H., Koch U., Blacklow S.C., Palmer H.G., Bornhauser B., González-Gaitán M., Arsenijevic Y., Zoete V., Aster J.C., Bourquin J.P., Radtke F.
ISSN
1091-6490 (Electronic)
ISSN-L
0027-8424
Publication state
Published
Issued date
14/07/2020
Peer-reviewed
Oui
Volume
117
Number
28
Pages
16292-16301
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Notch pathway signaling is implicated in several human cancers. Aberrant activation and mutations of Notch signaling components are linked to tumor initiation, maintenance, and resistance to cancer therapy. Several strategies, such as monoclonal antibodies against Notch ligands and receptors, as well as small-molecule γ-secretase inhibitors (GSIs), have been developed to interfere with Notch receptor activation at proximal points in the pathway. However, the use of drug-like small molecules to target the downstream mediators of Notch signaling, the Notch transcription activation complex, remains largely unexplored. Here, we report the discovery of an orally active small-molecule inhibitor (termed CB-103) of the Notch transcription activation complex. We show that CB-103 inhibits Notch signaling in primary human T cell acute lymphoblastic leukemia and other Notch-dependent human tumor cell lines, and concomitantly induces cell cycle arrest and apoptosis, thereby impairing proliferation, including in GSI-resistant human tumor cell lines with chromosomal translocations and rearrangements in Notch genes. CB-103 produces Notch loss-of-function phenotypes in flies and mice and inhibits the growth of human breast cancer and leukemia xenografts, notably without causing the dose-limiting intestinal toxicity associated with other Notch inhibitors. Thus, we describe a pharmacological strategy that interferes with Notch signaling by disrupting the Notch transcription complex and shows therapeutic potential for treating Notch-driven cancers.
Keywords
Notch, cancer, small-molecule inhbitor
Pubmed
Web of science
Create date
03/07/2020 17:11
Last modification date
28/09/2020 14:12
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