%0 Journal Article
%A Kamada, Yusuke
%A Sakai, Nozomu
%A Sogabe, Satoshi
%A Ida, Koh
%A Oki, Hideyuki
%A Sakamoto, Kotaro
%A Lane, Weston
%A Snell, Gyorgy
%A Iida, Motoo
%A Imaeda, Yasuhiro
%A Sakamoto, Junichi
%A Matsui, Junji
%D 2017
%T Discovery of a
B‑Cell Lymphoma 6 Protein–Protein
Interaction Inhibitor by a Biophysics-Driven Fragment-Based Approach
%U 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
%R 10.1021/acs.jmedchem.7b00313.s001
%2 https://acs.figshare.com/ndownloader/files/8413025
%K compound 7
%K ligand BCoR peptide
%K PPI IC 50
%K lymphocytes
%K transcriptional factor
%K structure-based design
%K fragment 1
%K cancer treatment
%K interaction
%K 0.078 μ M
%K high-throughput screening
%K 8.6 μ M
%K ELISA
%K SPR K D
%K Biophysics-Driven Fragment-Based Approach B-cell lymphoma 6
%K surface plasmon resonance
%K IC 50
%K LE
%K M 2H
%K BCL 6
%K 0.48 μ M
%K 1200 μ M
%K ligand efficiency
%K biophysics-driven fragment-based approach
%X 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 1 (SPR KD = 1200 μM, ligand efficiency
(LE) = 0.28), a competitive binder to the natural ligand BCoR peptide.
Moreover, we elaborated 1 into the more potent compound 7 (SPR KD = 0.078 μM, LE
= 0.37, cell-free protein–protein interaction (PPI) IC50 = 0.48 μM (ELISA), cellular PPI IC50 =
8.6 μM (M2H)) by a structure-based design and structural integration
with a second high-throughput screening hit.
%I ACS Publications