University of Cambridge
Small molecule-degrader conjugates for MALAT1 triplex degradation
Abstract
dc:description.abstractMetastasis is the primary cause of death associated with oncological disease. However, the biological processes of metastasis still need to be fully rationalised and understood. The insurgence of secondary neoplasms for numerous types of cancer has been correlated multiple times to the overexpression of a specific, long non-coding RNA sequence called MALAT1. Due to its uncommon triple helix structure, this transcript has a noteworthy stability, with a half-life of up to 15 hours, resulting in its build-up in the cell environment. This work details my efforts in the design and synthesis of efficient small molecule drugs based on the PINAD (Proximity Induced Nucleic Acid Degrader) technology for the selective targeting and cleavage of the uncommon secondary triple helix structure found at the 3’ end of human MALAT1 (Metastasis Associated Lung Adenocarcinoma Transcript 1) RNA transcript. Taking advantage of the peculiar architecture composing the ENE+A tract of MALAT1, we prepared a small molecule that targets this transcript with an elevated level of selectivity due to its duplicitous nature of conjugate merging a MALAT1 specific binder and an imidazole-based warhead for RNA degradation. Furthermore, we present the results of some standard biophysical and biological assays that provide empirical proofs of the efficacy of our compounds in the cleavage of MALAT1 and, more generally, of the value of the PINAD technology for the degradation of RNA transcripts.
Degree
thesis:*- Name dc:type.qualificationname
- Doctor of Philosophy (PhD)
- Level dc:type.qualificationlevel
- Doctoral
- Grantor dc:publisher.institution
- University of Cambridge
- Year dc:date.issued
- 2025
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Turin Brega, Christian
- Advisor dc:contributor.advisor
-
- Bernardes, Gonçalo
Subjects
dc:subject × 7Rights
dc:rightsIdentifiers
dc:identifier.*- DOI dc:identifier.doi
- https://doi.org/10.17863/CAM.115887
- OAI identifier oai:identifier
- oai:www.repository.cam.ac.uk:1810/379916