9T0T

Crystal Structure of the correct enantiomer bound to the PH domain of Btk

This is a non-PDB format compatible entry.

Summary for 9T0T

• Entry DOI: 10.2210/pdb9t0t/pdb
• Descriptor: Tyrosine-protein kinase BTK, (6~{R})-6-(2-bromanyl-6-chloranyl-phenyl)-4-oxidanylidene-6,7-dihydro-5~{H}-1-benzofuran-3-carboxylic acid, (6~{R})-6-(2-bromanyl-6-chloranyl-phenyl)-4,5,6,7-tetrahydro-1-benzofuran-3-carboxylic acid, ... (6 entities in total)
• Functional Keywords: fragment based drug discovery, ph domain, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 82374.30

Authors

Brear, P.,West, R.M.,Nicolescu, R.C.B.,Blaszczyk, B.K.,Anwar, A.,Deingruber, T.,Sanders, M.G.,Perez-Areales, F.J.,Stephens, L.R.,Hawkins, P.T.,Spring, D.R.,Hyvonen, M. (deposition date: 2025-10-20, release date: 2026-05-27, Last modification date: 2026-06-03)

Primary citation

West, R.M.,Bizga Nicolescu, R.C.,Brear, P.,Wagstaff, J.,Blaszczyk, B.K.,Deingruber, T.,Sanders, M.G.,Perez-Areales, F.J.,Spring, D.R.,Hyvonen, M.
Targeting a Pleckstrin Homology Domain with a Lysine-Reactive Covalent Binder.
J.Med.Chem., 69:12099-12121, 2026

PubMed Abstract: Bruton's Tyrosine Kinase (BTK) is a validated target for hematological malignancies, with numerous FDA-approved inhibitors on the market. Current therapies target the highly conserved ATP binding site and hence limit the therapeutic index given the site's highly conserved nature across the kinome. We explore a novel approach for BTK inhibition by targeting the PH domain-mediated membrane recruitment and activation of BTK. We have identified a fragment which covalently modifies a lysine in the inositol phosphate (PIP3) binding site and inhibits the binding of a soluble PIP3 headgroup analog to the PH domain. Fragment growth and an extensive structure-binding relationship study uncovered 27 crystal structures and a best-in-class analog, . Evaluation of p values of the targeted lysine in BTK and other PH domains suggests this as a more general approach to PH domain inhibition.

PubMed: 42130460
DOI: 10.1021/acs.jmedchem.5c03818

Experimental method

X-RAY DIFFRACTION (1.73 Å)