9D12

Smarca2 Bromodomain in complex with compound 15

This is a non-PDB format compatible entry.

Summary for 9D12

• Entry DOI: 10.2210/pdb9d12/pdb
• Descriptor: Isoform Short of Probable global transcription activator SNF2L2, ZINC ION, (12'R)-4'-chloro-9'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one, ... (5 entities in total)
• Functional Keywords: smarca2, brm, swi/snf, bromodomain, gene regulation
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 3
• Total formula weight: 44936.78

Authors

Meagher, J.L.,Stuckey, J.A. (deposition date: 2024-08-07, release date: 2025-01-15, Last modification date: 2025-02-05)

Primary citation

Leng, L.,Tu, W.,Yang, L.,Huang, L.,Wang, M.,Meagher, J.L.,Chinnaswamy, K.,Allu, S.R.,Rej, R.K.,Tosovic, J.,Harikrishnan, L.,Li, Z.,Sui, Z.,Stuckey, J.A.,Wang, S.
Discovery of High-Affinity SMARCA2/4 Bromodomain Ligands and Development of Potent and Exceptionally Selective SMARCA2 PROTAC Degraders.
J.Med.Chem., 68:1113-1133, 2025

PubMed Abstract: In the SWI/SNF chromatin-remodeling complex, the mutually exclusive catalytic ATPase subunits SMARCA2 and SMARCA4 proteins have a synthetic-lethal relationship. Selectively targeting SMARCA2 for degradation is a promising and new therapeutic strategy for human cancers harboring inactivated mutated SMARCA4. In this study, we report the design, synthesis, and biological evaluation of novel SMARCA2/4 ligands and our subsequent design of PROTAC degraders using high-affinity SMARCA ligands and VHL-1 ligands. Our efforts led to the discovery of high-affinity SMARCA2/4 bromodomain ligands and the development of a potent and selective SMARCA2 degrader and a highly potent SMARCA2/4 and PBRM1 degrader.

PubMed: 39745064
DOI: 10.1021/acs.jmedchem.4c01903

Experimental method

X-RAY DIFFRACTION (2.099 Å)