Issue 45, 2023

Identification of non-conventional small molecule degraders and stabilizers of squalene synthase

Abstract

Squalene synthase (SQS) is an essential enzyme in the mevalonate pathway, which controls cholesterol biosynthesis and homeostasis. Although catalytic inhibitors of SQS have been developed, none have been approved for therapeutic use so far. Herein we sought to develop SQS degraders using targeted protein degradation (TPD) to lower overall cellular cholesterol content. We found that KY02111, a small molecule ligand of SQS, selectively causes SQS to degrade in a proteasome-dependent manner. Unexpectedly, compounds based on the same scaffold linked to E3 ligase recruiting ligands led to SQS stabilization. Proteomic analysis found KY02111 to reduce only the levels of SQS, while lipidomic analysis determined that KY02111-induced degradation lowered cellular cholesteryl ester content. Stabilizers shielded SQS from its natural turnover without recruiting their matching E3 ligase or affecting enzymatic target activity. Our work shows that degradation of SQS is possible despite a challenging biological setting and provides the first chemical tools to degrade and stabilize SQS.

Graphical abstract: Identification of non-conventional small molecule degraders and stabilizers of squalene synthase

Supplementary files

Article information

Article type
Edge Article
Submitted
04 8 2023
Accepted
15 10 2023
First published
18 10 2023
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2023,14, 12973-12983

Identification of non-conventional small molecule degraders and stabilizers of squalene synthase

J. G. F. Hoock, C. Rossetti, M. Bilgin, L. Depta, K. Enemark-Rasmussen, J. C. Christianson and L. Laraia, Chem. Sci., 2023, 14, 12973 DOI: 10.1039/D3SC04064J

This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. You can use material from this article in other publications, without requesting further permission from the RSC, provided that the correct acknowledgement is given and it is not used for commercial purposes.

To request permission to reproduce material from this article in a commercial publication, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party commercial publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements