A Unique Approach
to Design Potent and Selective Cyclic
Adenosine Monophosphate Response Element Binding Protein, Binding
Protein (CBP) Inhibitors
Sarah M. Bronner
Jeremy Murray
F. Anthony Romero
Kwong Wah Lai
Vickie Tsui
Patrick Cyr
Maureen H. Beresini
Gladys de leon Boenig
Zhongguo Chen
Edna F. Choo
Kevin R. Clark
Terry D. Crawford
Hariharan Jayaram
Susan Kaufman
Ruina Li
Yingjie Li
Jiangpeng Liao
Xiaorong Liang
Wenfeng Liu
Justin Ly
Jonathan Maher
John Wai
Fei Wang
Aijun Zheng
Xiaoyu Zhu
Steven Magnuson
10.1021/acs.jmedchem.7b01372.s001
https://acs.figshare.com/articles/journal_contribution/A_Unique_Approach_to_Design_Potent_and_Selective_Cyclic_Adenosine_Monophosphate_Response_Element_Binding_Protein_Binding_Protein_CBP_Inhibitors/5688436
The
epigenetic regulator CBP/P300 presents a novel therapeutic
target for oncology. Previously, we disclosed the development of potent
and selective CBP bromodomain inhibitors by first identifying pharmacophores
that bind the KAc region and then building into the LPF shelf. Herein,
we report the “hybridization” of a variety of KAc-binding
fragments with a tetrahydroquinoline scaffold that makes optimal interactions
with the LPF shelf, imparting enhanced potency and selectivity to
the hybridized ligand. To demonstrate the utility of our hybridization
approach, two analogues containing unique Asn binders and the optimized
tetrahydroquinoline moiety were rapidly optimized to yield single-digit
nanomolar inhibitors of CBP with exquisite selectivity over BRD4(1)
and the broader bromodomain family.
2017-11-20 00:00:00
selectivity
CBP bromodomain inhibitors
LPF shelf
hybridization
BRD
Selective Cyclic Adenosine Monophosphate Response Element Binding Protein
optimized tetrahydroquinoline moiety