9QAD

Crystal structure of the SMARCA2 bromodomain bound to a tricyclic pyrimidoindolone inhibitor (compound 17)

This is a non-PDB format compatible entry.

Summary for 9QAD

• Entry DOI: 10.2210/pdb9qad/pdb
• Descriptor: Probable global transcription activator SNF2L2, 5-oxidanyl-2-(phenylmethyl)-1,9-dihydropyrimido[4,5-b]indol-4-one, ZINC ION, ... (4 entities in total)
• Functional Keywords: bromodomain, fragment screening, structure-based inhibitor design, gene regulation
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 3
• Total formula weight: 44211.76

Authors

Schimpl, M. (deposition date: 2025-02-28, release date: 2025-05-14, Last modification date: 2025-07-02)

Primary citation

Boerth, J.A.,Schimpl, M.,Lucas, S.C.C.,Zhang, J.,Code, E.L.,Embrey, K.J.,Rawlins, P.B.,Wang, H.,Storer, R.I.,Di Fruscia, P.,Nelson, J.E.,Milbradt, A.G.,Borjesson, U.,Gohlke, A.,Korboukh, V.,Gopalsamy, A.
Discovery of Pyrimidoindolones as Novel Family VIII Bromodomain Binders.
Acs Med.Chem.Lett., 16:1073-1079, 2025

PubMed 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.

PubMed: 40529061
DOI: 10.1021/acsmedchemlett.5c00120

Experimental method

X-RAY DIFFRACTION (2.08 Å)