9FL0

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

This is a non-PDB format compatible entry.

Summary for 9FL0

• Entry DOI: 10.2210/pdb9fl0/pdb
• Descriptor: Bcl-2-related protein A1, ~{N}-[(4-chlorophenyl)methyl]-~{N}-(4-fluorophenyl)prop-2-enamide (3 entities in total)
• Functional Keywords: bfl-1, bcl-2-related protein a1, covalent, apoptosis
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 35465.24

Authors

Hargreaves, D. (deposition date: 2024-06-04, release date: 2024-10-02, Last modification date: 2024-10-09)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.94 Å)