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. 2025 May 8;16(6):1073-1079.
doi: 10.1021/acsmedchemlett.5c00120. eCollection 2025 Jun 12.

Discovery of Pyrimidoindolones as Novel Family VIII Bromodomain Binders

Jeffrey A Boerth  1 , Marianne Schimpl  2 , Simon C C Lucas  3 , Jingwen Zhang  4 , Erin L Code  5 , Kevin J Embrey  6 , Philip B Rawlins  2 , Haixia Wang  1 , R Ian Storer  3 , Paolo Di Fruscia  3 , Jennifer E Nelson  3 , Alexander G Milbradt  7 , Ulf Börjesson  8 , Andrea Gohlke  2 , Victoria Korboukh  5 , Ariamala Gopalsamy  1
Affiliations

Discovery of Pyrimidoindolones as Novel Family VIII Bromodomain Binders

Jeffrey A Boerth et al. ACS Med Chem Lett. .

Abstract

Suppression of oncogenic gene expression is an effective strategy for the treatment of cancer. The SWI/SNF (SWItch/Sucrose Non-Fermentable) complex plays an important role in regulating gene activation or repression, and its dysregulation has been linked to aberrant transcription activity in many types of cancer. Targeting the subunits of this complex, such as SMARCA2, SMARCA4, and PBRM1, which are part of the bromodomain family VIII, has significant therapeutic potential. Herein we report the discovery of pyrimidoindolones as a novel series of bromodomain family VIII binders identified through an NMR-based fragment screen. These binders have been optimized to achieve sub-μM affinity for the family VIII proteins SMARCA2, SMARCA4, and PRBM1, with promising physicochemical properties.

Keywords: Bromodomain binders; NMR fragment screening; PBRM1; Pyrimidoindolones; SMARCA2; SMARCA4.

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