9E1K

Discovery of Potent, Highly Selective and Efficacious SMARCA2 Degraders - Compound 11

これはPDB形式変換不可エントリーです。

9E1K の概要

• エントリーDOI: 10.2210/pdb9e1k/pdb
• 分子名称: Isoform Short of Probable global transcription activator SNF2L2, (12S)-4-bromo-7,7-dimethyl-9-(piperidin-4-yl)indolo[1,2-a]quinazolin-5(7H)-one, ZINC ION, ... (4 entities in total)
• 機能のキーワード: protein degrader, transcription
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 44610.85

構造登録者

Strickland, C.,Rice, C. (登録日: 2024-10-21, 公開日: 2024-12-18)

主引用文献

Li, Z.,Harikrishnan, L.S.,Xu, G.,Samanta, D.,Clemente, J.C.,Leng, L.,Tu, W.,Yang, L.,Huang, L.,Wang, M.,Wang, S.,Deng, Q.,Behshad, E.,Nagilla, R.,Orth, P.,Rice, C.,Strickland, C.,Mohammad, H.P.,Priestley, E.S.,Sui, Z.
Discovery of Potent, Highly Selective, and Efficacious SMARCA2 Degraders.
J.Med.Chem., 2024

PubMed Abstract: We describe the identification of selective SMARCA2, VHL-based heterobifunctional degraders. Structurally novel indolo[1,2-]quinazolin-5(7)-one SMARCA bromodomain binders were optimized and then converted to SMARCA2 degraders by linking them to well-defined VHL ligands. Our exploration led to the discovery of potent and selective degraders of SMARCA2 over the SMARCA4 paralog, leading to potent and selective growth inhibition of SMARCA4 mutant versus wild type cell lines. We further highlight the optimization of the pharmacokinetic profile of a subset of compounds leading to potent and selective degradation of SMARCA2 in the xenograft model. These compounds provide valuable tools with desirable properties for continued exploration of the biology defining the susceptibility of SMARCA4 mutant cancers to selective loss of SMARCA2.

PubMed: 39570797
DOI: 10.1021/acs.jmedchem.4c01878

実験手法

X-RAY DIFFRACTION (2.26 Å)