9FL0

Discovery of a Series of Covalent, Cell Active Bfl-1 Inhibitors

これはPDB形式変換不可エントリーです。

9FL0 の概要

• エントリーDOI: 10.2210/pdb9fl0/pdb
• 分子名称: Bcl-2-related protein A1, ~{N}-[(4-chlorophenyl)methyl]-~{N}-(4-fluorophenyl)prop-2-enamide (3 entities in total)
• 機能のキーワード: bfl-1, bcl-2-related protein a1, covalent, apoptosis
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 35465.24

構造登録者

Hargreaves, D. (登録日: 2024-06-04, 公開日: 2024-10-02, 最終更新日: 2024-10-09)

主引用文献

Lucas, S.C.C.,Blackwell, J.H.,Borjesson, U.,Hargreaves, D.,Milbradt, A.G.,Bostock, M.J.,Ahmed, S.,Beaumont, K.,Cheung, T.,Demanze, S.,Gohlke, A.,Guerot, C.,Haider, A.,Kantae, V.,Kauffman, G.W.,Kinzel, O.,Kupcova, L.,Lainchbury, M.D.,Lamb, M.L.,Leon, L.,Palisse, A.,Sacchetto, C.,Storer, R.I.,Su, N.,Thomson, C.,Vales, J.,Chen, Y.,Hu, X.
Structure-Based Optimization of a Series of Covalent, Cell Active Bfl-1 Inhibitors.
J.Med.Chem., 67:16455-16479, 2024

PubMed Abstract: Bfl-1, a member of the Bcl-2 family of proteins, plays a crucial role in apoptosis regulation and has been implicated in cancer cell survival and resistance to venetoclax therapy. Due to the unique cysteine residue in the BH3 binding site, the development of covalent inhibitors targeting Bfl-1 represents a promising strategy for cancer treatment. Herein, the optimization of a covalent cellular tool from a lead-like hit using structure based design is described. Informed by a reversible X-ray fragment screen, the strategy to establish interactions with a key glutamic acid residue (Glu78) and optimize binding in a cryptic pocket led to a 1000-fold improvement in biochemical potency without increasing reactivity of the warhead. Compound has a of 4600 M s, shows <1 μM caspase activation in a cellular assay and cellular target engagement, and has good physicochemical properties and a promising profile.

PubMed: 39291659
DOI: 10.1021/acs.jmedchem.4c01288

実験手法

X-RAY DIFFRACTION (1.94 Å)