Discovery of a
B‑Cell Lymphoma 6 Protein–Protein
Interaction Inhibitor by a Biophysics-Driven Fragment-Based Approach
Yusuke Kamada
Nozomu Sakai
Satoshi Sogabe
Koh Ida
Hideyuki Oki
Kotaro Sakamoto
Weston Lane
Gyorgy Snell
Motoo Iida
Yasuhiro Imaeda
Junichi Sakamoto
Junji Matsui
10.1021/acs.jmedchem.7b00313.s001
https://acs.figshare.com/articles/journal_contribution/Discovery_of_a_B_Cell_Lymphoma_6_Protein_Protein_Interaction_Inhibitor_by_a_Biophysics-Driven_Fragment-Based_Approach/4996712
B-cell lymphoma 6 (BCL6) is a transcriptional
factor that expresses
in lymphocytes and regulates the differentiation and proliferation
of lymphocytes. Therefore, BCL6 is a therapeutic target for autoimmune
diseases and cancer treatment. This report presents the discovery
of BCL6–corepressor interaction inhibitors by using a biophysics-driven
fragment-based approach. Using the surface plasmon resonance (SPR)-based
fragment screening, we successfully identified fragment <b>1</b> (SPR <i>K</i><sub>D</sub> = 1200 μM, ligand efficiency
(LE) = 0.28), a competitive binder to the natural ligand BCoR peptide.
Moreover, we elaborated <b>1</b> into the more potent compound <b>7</b> (SPR <i>K</i><sub>D</sub> = 0.078 μM, LE
= 0.37, cell-free protein–protein interaction (PPI) IC<sub>50</sub> = 0.48 μM (ELISA), cellular PPI IC<sub>50</sub> =
8.6 μM (M2H)) by a structure-based design and structural integration
with a second high-throughput screening hit.
2017-05-04 00:00:00
compound 7
ligand BCoR peptide
PPI IC 50
lymphocytes
transcriptional factor
structure-based design
fragment 1
cancer treatment
interaction
0.078 μ M
high-throughput screening
8.6 μ M
ELISA
SPR K D
Biophysics-Driven Fragment-Based Approach B-cell lymphoma 6
surface plasmon resonance
IC 50
LE
M 2H
BCL 6
0.48 μ M
1200 μ M
ligand efficiency
biophysics-driven fragment-based approach