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. 2025 Dec 1:128:130326.
doi: 10.1016/j.bmcl.2025.130326. Epub 2025 Jul 3.

Orthosteric inhibition of MutSβ ATPase function: First disclosure of MSH3-bound small molecule inhibitors

Gareth N Brace  1 , Karsten Tillack  2 , Peter D Johnson  1 , Markus Ritzefeld  2 , Sabine Schaertl  2 , Elizabeth Frush  3 , Becka Warfield  3 , George Ballantyne  1 , Jung-Hoon Lee  4 , Gabriel Thieulin-Pardo  4 , Stefan Steinbacher  4 , Maren Thomsen  4 , David Witte  4 , Michael Finley  5 , Brinda C Prasad  5 , Edith Monteagudo  5 , Nikolay V Plotnikov  5 , Robert E Pacifici  5 , Michel Maillard  5 , Hilary A Wilkinson  5 , Ravi R Iyer  5 , Celia Dominguez  5 , Thomas F Vogt  5 , Dan P Felsenfeld  6 , Tasir S Haque  7
Affiliations

Orthosteric inhibition of MutSβ ATPase function: First disclosure of MSH3-bound small molecule inhibitors

Gareth N Brace et al. Bioorg Med Chem Lett. .

Abstract

Orthosteric inhibitors of the human heterodimeric DNA mismatch repair complex MutSβ were identified by high-throughput screening. Following extensive hit confirmation to remove false positives, two series were found to give consistent activity free of likely artefactual effects. Extensive hit profiling confirmed an ATP-competitive mode of action and resulted in our obtaining the first reported X-ray and cryo-EM structures of small molecule inhibitors of MutSβ occupying the ATP-binding site of MSH3.

Keywords: ATPase; DNA mismatch repair; High-throughput screening; Huntington's disease; MSH3; MutSβ; Screening cascade.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: George Ballantyne, Gareth Brace, Elizabeth Frush, Michel Maillard, and Tasir Haque have patent #WO 2024/118607 Al pending to CHDI Foundation, Inc. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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