Issue 21, 2024

Cell-active small molecule inhibitors validate the SNM1A DNA repair nuclease as a cancer target

Abstract

The three human SNM1 metallo-β-lactamase fold nucleases (SNM1A–C) play key roles in DNA damage repair and in maintaining telomere integrity. Genetic studies indicate that they are attractive targets for cancer treatment and to potentiate chemo- and radiation-therapy. A high-throughput screen for SNM1A inhibitors identified diverse pharmacophores, some of which were shown by crystallography to coordinate to the di-metal ion centre at the SNM1A active site. Structure and turnover assay-guided optimization enabled the identification of potent quinazoline–hydroxamic acid containing inhibitors, which bind in a manner where the hydroxamic acid displaces the hydrolytic water and the quinazoline ring occupies a substrate nucleobase binding site. Cellular assays reveal that SNM1A inhibitors cause sensitisation to, and defects in the resolution of, cisplatin-induced DNA damage, validating the tractability of MBL fold nucleases as cancer drug targets.

Graphical abstract: Cell-active small molecule inhibitors validate the SNM1A DNA repair nuclease as a cancer target

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Article information

Article type
Edge Article
Submitted
16 Jan 2024
Accepted
30 Mar 2024
First published
30 Apr 2024
This article is Open Access

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

Chem. Sci., 2024,15, 8227-8241

Cell-active small molecule inhibitors validate the SNM1A DNA repair nuclease as a cancer target

M. Bielinski, L. R. Henderson, Y. Yosaatmadja, L. P. Swift, H. T. Baddock, M. J. Bowen, J. Brem, P. S. Jones, S. P. McElroy, A. Morrison, M. Speake, S. van Boeckel, E. van Doornmalen, J. van Groningen, H. van den Hurk, O. Gileadi, J. A. Newman, P. J. McHugh and C. J. Schofield, Chem. Sci., 2024, 15, 8227 DOI: 10.1039/D4SC00367E

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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