8QJR

BRG1 bromodomain in complex with VBC via compound 17

Summary for 8QJR

• Entry DOI: 10.2210/pdb8qjr/pdb
• Descriptor: Elongin-B, Elongin-C, von Hippel-Lindau disease tumor suppressor, ... (9 entities in total)
• Functional Keywords: brg1, bromodomain, vhl, elongin, vbc, e3 ligase, von hippel-lindau, ubiquitinase, gene regulation
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 114240.45

Authors

Kerry, P.S.,Hole, A.J.,Perez-Dorado, J.I. (deposition date: 2023-09-13, release date: 2024-01-17, Last modification date: 2024-02-07)

Primary citation

Berlin, M.,Cantley, J.,Bookbinder, M.,Bortolon, E.,Broccatelli, F.,Cadelina, G.,Chan, E.W.,Chen, H.,Chen, X.,Cheng, Y.,Cheung, T.K.,Davenport, K.,DiNicola, D.,Gordon, D.,Hamman, B.D.,Harbin, A.,Haskell, R.,He, M.,Hole, A.J.,Januario, T.,Kerry, P.S.,Koenig, S.G.,Li, L.,Merchant, M.,Perez-Dorado, I.,Pizzano, J.,Quinn, C.,Rose, C.M.,Rousseau, E.,Soto, L.,Staben, L.R.,Sun, H.,Tian, Q.,Wang, J.,Wang, W.,Ye, C.S.,Ye, X.,Zhang, P.,Zhou, Y.,Yauch, R.,Dragovich, P.S.
PROTACs Targeting BRM (SMARCA2) Afford Selective In Vivo Degradation over BRG1 (SMARCA4) and Are Active in BRG1 Mutant Xenograft Tumor Models.
J.Med.Chem., 67:1262-1313, 2024

PubMed Abstract: The identification of VHL-binding proteolysis targeting chimeras (PROTACs) that potently degrade the BRM protein (also known as SMARCA2) in SW1573 cell-based experiments is described. These molecules exhibit between 10- and 100-fold degradation selectivity for BRM over the closely related paralog protein BRG1 (SMARCA4). They also selectively impair the proliferation of the H1944 "BRG1-mutant" NSCLC cell line, which lacks functional BRG1 protein and is thus highly dependent on BRM for growth, relative to the wild-type Calu6 line. experiments performed with a subset of compounds identified PROTACs that potently and selectively degraded BRM in the Calu6 and/or the HCC2302 BRG1 mutant NSCLC xenograft models and also afforded antitumor efficacy in the latter system. Subsequent PK/PD analysis established a need to achieve strong BRM degradation (>95%) in order to trigger meaningful antitumor activity . Intratumor quantitation of mRNA associated with two genes whose transcription was controlled by BRM ( and ) also supported this conclusion.

PubMed: 38180485
DOI: 10.1021/acs.jmedchem.3c01781

Experimental method

X-RAY DIFFRACTION (3.17 Å)