Fragment-Based Discovery of Novel MUS81 Inhibitors.

Autor:	Collie GW; R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Börjesson U; R&D, AstraZeneca, Gothenburg 431 83, Sweden., Chen Y; Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing 100176, P.R. China., Dong Z; Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing 100176, P.R. China., Di Fruscia P; R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Gohlke A; R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Hoyle A; R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Hunt TA; R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Jesani MH; R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Luo H; Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing 100176, P.R. China., Luptak J; R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Milbradt AG; R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Narasimhan P; R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Packer M; R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Patel S; R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Qiao J; Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing 100176, P.R. China., Storer RI; R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Stubbs CJ; R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Tart J; R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Truman C; R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Wang AT; R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Wheeler MG; R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Winter-Holt J; R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2024 Jun 07; Vol. 15 (7), pp. 1151-1158. Date of Electronic Publication: 2024 Jun 07 (Print Publication: 2024).
DOI:	10.1021/acsmedchemlett.3c00453
Abstrakt:	MUS81 is a structure-selective endonuclease that cleaves various branched DNA structures arising from natural physiological processes such as homologous recombination and mitosis. Due to this, MUS81 is able to relieve replication stress, and its function has been reported to be critical to the survival of many cancers, particularly those with dysfunctional DNA-repair machinery. There is therefore interest in MUS81 as a cancer drug target, yet there are currently few small molecule inhibitors of this enzyme reported, and no liganded crystal structures are available to guide hit optimization. Here we report the fragment-based discovery of novel small molecule MUS81 inhibitors with sub-μM biochemical activity. These inhibitors were used to develop a novel crystal system, providing the first structural insight into the inhibition of MUS81 with small molecules. Competing Interests: The authors declare no competing financial interest. (© 2024 The Authors. Published by American Chemical Society.)
Databáze:	MEDLINE
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