6EG3

Crystal structure of human BRM in complex with compound 15

Summary for 6EG3

• Entry DOI: 10.2210/pdb6eg3/pdb
• Descriptor: Maltose/maltodextrin-binding periplasmic protein,Probable global transcription activator SNF2L2, 3-[(4-{[(2-chloropyridin-4-yl)carbamoyl]amino}pyridin-2-yl)ethynyl]benzoic acid, ETHANOL, ... (4 entities in total)
• Functional Keywords: helicase, atpase, chromatin remodeling, inhibitor, mbp fusion, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Escherichia coli O157:H7; More
• Total number of polymer chains: 1
• Total formula weight: 70322.26

Authors

Zhu, X.,Kulathila, R.,Hu, T.,Xie, X. (deposition date: 2018-08-17, release date: 2018-10-31, Last modification date: 2023-10-11)

Primary citation

Papillon, J.P.N.,Nakajima, K.,Adair, C.D.,Hempel, J.,Jouk, A.O.,Karki, R.G.,Mathieu, S.,Mobitz, H.,Ntaganda, R.,Smith, T.,Visser, M.,Hill, S.E.,Hurtado, F.K.,Chenail, G.,Bhang, H.C.,Bric, A.,Xiang, K.,Bushold, G.,Gilbert, T.,Vattay, A.,Dooley, J.,Costa, E.A.,Park, I.,Li, A.,Farley, D.,Lounkine, E.,Yue, Q.K.,Xie, X.,Zhu, X.,Kulathila, R.,King, D.,Hu, T.,Vulic, K.,Cantwell, J.,Luu, C.,Jagani, Z.
Discovery of Orally Active Inhibitors of Brahma Homolog (BRM)/SMARCA2 ATPase Activity for the Treatment of Brahma Related Gene 1 (BRG1)/SMARCA4-Mutant Cancers.
J. Med. Chem., 61:10155-10172, 2018

PubMed Abstract: SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily A member 2 (SMARCA2), also known as Brahma homologue (BRM), is a Snf2-family DNA-dependent ATPase. BRM and its close homologue Brahma-related gene 1 (BRG1), also known as SMARCA4, are mutually exclusive ATPases of the large ATP-dependent SWI/SNF chromatin-remodeling complexes involved in transcriptional regulation of gene expression. No small molecules have been reported that modulate SWI/SNF chromatin-remodeling activity via inhibition of its ATPase activity, an important goal given the well-established dependence of BRG1-deficient cancers on BRM. Here, we describe allosteric dual BRM and BRG1 inhibitors that downregulate BRM-dependent gene expression and show antiproliferative activity in a BRG1-mutant-lung-tumor xenograft model upon oral administration. These compounds represent useful tools for understanding the functions of BRM in BRG1-loss-of-function settings and should enable probing the role of SWI/SNF functions more broadly in different cancer contexts and those of other diseases.

PubMed: 30339381
DOI: 10.1021/acs.jmedchem.8b01318

Experimental method

X-RAY DIFFRACTION (2.84 Å)