Probing the druggability of the Notch1 ankyrin domain using a fragment-based approach
type: CreativeWork
description: Notch signalling is a highly conserved pathway that is important in the developmental processes that control cell differentiation and cell fates. This canonical pathway involves binding of a transmembrane ligand in one cell to the extraceullular domain of a transmembrane Notch receptor in an adjacent cell. Ligand binding triggers two sequential proteolytic cleavages that shed a Notch intracellular domain (NICD). This is followed by translocation of NICD to the nucleus where it interacts with a transcription factor CSL and forms an activated Notch transcription complex, which induces the transcription of Notch target genes. Abnormal expression or mutations in the different components of the pathway are associated with a number of diseases and cancers. An enhanced activity of Notch signalling resulting from a mutation in the extracellular domain is implicated in the progression of T-acute lymphoblastic leukaemia (T-ALL). Several therapeutic agents have been developed to target the Notch signalling pathway such as, γ-secretase inhibitors, antibodies targeting different regions of the Notch receptor and recently a synthetic stapled peptide, which was found to inhibit the formation of the transcription complex. The current inhibitors have their own disadvantages including lack of selectivity, cost of goods and delivery to the target. Thus, a more selective approach to target downstream proteinprotein interactions by small molecules would provide an attractive approach to the design of new therapeutic agents that target this pathway. Here I report a fragment-based approach to target the ankyrin domain, a historically known but challenging, often-considered “undruggable” target. In this dissertation I describe the application of various biophysical and computational approaches to find, characterise and design compounds. The initial screening of a commercial fragment-library exploited a fluorescent-based thermal shift assay that identified 36 fragment hits. Some of the frag…
abstract: Notch signalling is a highly conserved pathway that is important in the developmental processes that control cell differentiation and cell fates. This canonical pathway involves binding of a transmembrane ligand in one cell to the extraceullular domain of a transmembrane Notch receptor in an adjacent cell. Ligand binding triggers two sequential proteolytic cleavages that shed a Notch intracellular domain (NICD). This is followed by translocation of NICD to the nucleus where it interacts with a transcription factor CSL and forms an activated Notch transcription complex, which induces the transcription of Notch target genes. Abnormal expression or mutations in the different components of the pathway are associated with a number of diseases and cancers. An enhanced activity of Notch signalling resulting from a mutation in the extracellular domain is implicated in the progression of T-acute lymphoblastic leukaemia (T-ALL). Several therapeutic agents have been developed to target the Notch signalling pathway such as, γ-secretase inhibitors, antibodies targeting different regions of the Notch receptor and recently a synthetic stapled peptide, which was found to inhibit the formation of the transcription complex. The current inhibitors have their own disadvantages including lack of selectivity, cost of goods and delivery to the target. Thus, a more selective approach to target downstream proteinprotein interactions by small molecules would provide an attractive approach to the design of new therapeutic agents that target this pathway. Here I report a fragment-based approach to target the ankyrin domain, a historically known but challenging, often-considered “undruggable” target. In this dissertation I describe the application of various biophysical and computational approaches to find, characterise and design compounds. The initial screening of a commercial fragment-library exploited a fluorescent-based thermal shift assay that identified 36 fragment hits. Some of the frag…
author: Abdel-Rahman, Noha
language: eng
license: https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/b9258b51-1cf3-4c10-a358-a8e6f9a31a36/download
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2011-02-08
date modified: 2026-07-22T22:24:03Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.16524