6B3W

Structure of Hs/AcPRC2 in complex with 5,8-dichloro-7-(3,5-dimethyl-1,2-oxazol-4-yl)-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3,4-dihydroisoquinolin-1(2H)-one

6B3W の概要

• エントリーDOI: 10.2210/pdb6b3w/pdb
• 分子名称: Enhancer of zeste 2 polycomb repressive complex 2 subunit,Enhancer of zeste 2 polycomb repressive complex 2 subunit, Polycomb protein EED, Polycomb protein SUZ12, ... (5 entities in total)
• 機能のキーワード: lysine methyltransferase, metal binding protein
• 由来する生物種: Anolis carolinensis (Green anole); 詳細
• 細胞内の位置: Nucleus: O75530 Q15022
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 275781.91

構造登録者

Gajiwala, K.S.,Brooun, A.,Liu, W.,Deng, Y.,Stewart, A.E. (登録日: 2017-09-25, 公開日: 2017-12-27, 最終更新日: 2024-11-20)

主引用文献

Kung, P.P.,Bingham, P.,Brooun, A.,Collins, M.,Deng, Y.L.,Dinh, D.,Fan, C.,Gajiwala, K.S.,Grantner, R.,Gukasyan, H.J.,Hu, W.,Huang, B.,Kania, R.,Kephart, S.E.,Krivacic, C.,Kumpf, R.A.,Khamphavong, P.,Kraus, M.,Liu, W.,Maegley, K.A.,Nguyen, L.,Ren, S.,Richter, D.,Rollins, R.A.,Sach, N.,Sharma, S.,Sherrill, J.,Spangler, J.,Stewart, A.E.,Sutton, S.,Uryu, S.,Verhelle, D.,Wang, H.,Wang, S.,Wythes, M.,Xin, S.,Yamazaki, S.,Zhu, H.,Zhu, J.,Zehnder, L.,Edwards, M.
Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-5,8-Dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (PF-06821497).
J. Med. Chem., 61:650-665, 2018

PubMed Abstract: A new series of lactam-derived EZH2 inhibitors was designed via ligand-based and physicochemical-property-based strategies to address metabolic stability and thermodynamic solubility issues associated with previous lead compound 1. The new inhibitors incorporated an sp hybridized carbon atom at the 7-position of the lactam moiety present in lead compound 1 as a replacement for a dimethylisoxazole group. This transformation enabled optimization of the physicochemical properties and potency compared to compound 1. Analysis of relationships between calculated log D (clogD) values and in vitro metabolic stability and permeability parameters identified a clogD range that afforded an increased probability of achieving favorable ADME data in a single molecule. Compound 23a exhibited the best overlap of potency and pharmaceutical properties as well as robust tumor growth inhibition in vivo and was therefore advanced as a development candidate (PF-06821497). A crystal structure of 23a in complex with the three-protein PRC2 complex enabled understanding of the key structural features required for optimal binding.

PubMed: 29211475
DOI: 10.1021/acs.jmedchem.7b01375

実験手法

X-RAY DIFFRACTION (3.05 Å)