Design of Cyclic Vinyl Sulfones as WRN Covalent Inhibitors from Noncovalent Binders.

Justin A Caravella¹, Angela V Toms¹, Nikolay Sitnikov², Florian Bartels², Robert Svensson¹, Suzanne Jacques O'Hagan¹, Jennifer A Borthwick³, Sebastien Campos³, Ying Yin⁴, Xingwang Zhao⁴, Lezhen Li⁴, Ronggang Liu⁴, Eric Talbot³, Hanchu Kong⁴, Robert Reinhold Adolf Freund², Beth Browning¹, Nathan E Genung¹, Samantha Carreiro¹, Debra Brennan¹, Alan P Graves¹, Christine Loh¹, Peter Tummino¹, Scott D Edmondson¹, Derun Li¹

¹Nimbus Therapeutics, 22 Boston Wharf Rd. Floor 9, Boston, Massachusetts 02210, United States.

²Nuvisan ICB GmbH, Muellerstr. 178, 13353 Berlin, Germany.

³Pharmaron UK Ltd., West Hill Innovation Park, Hertford Road, Hoddesdon EN11 9FH, U.K.

⁴Department of Medicinal Chemistry, Pharmaron Beijing Co., Ltd., Beijing 100176, China.

PubMed DOI

Abstract

Werner syndrome helicase (WRN) is a DNA damage response protein selectively required for the survival of tumors with high microsatellite instability (MSI-H). We identified a noncovalent WRN inhibitor 1 via an extensive screening and hit triage. Co-crystal structure of 1 with the WRN helicase domain revealed a unique mechanism of inhibition via stabilization of inactive protein conformation and led…

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