15 research outputs found
Fragment-Based Discovery of Bromodomain Inhibitors Part 1: Inhibitor Binding Modes and Implications for Lead Discovery
Bromodomain-containing proteins are key epigenetic regulators
of gene transcription and readers of the histone code. However, the
therapeutic benefits of modulating this target class are largely unexplored
due to the lack of suitable chemical probes. This article describes
the generation of lead molecules for the BET bromodomains through
screening a fragment set chosen using structural insights and computational
approaches. Analysis of 40 BRD2/fragment X-ray complexes highlights
both shared and disparate interaction features that may be exploited
for affinity and selectivity. Six representative crystal structures
are then exemplified in detail. Two of the fragments are completely
new bromodomain chemotypes, and three have never before been crystallized
in a bromodomain, so our results significantly extend the limited
public knowledge-base of crystallographic small molecule/bromodomain
interactions. Certain fragments (including paracetamol) bind in a
consistent mode to different bromodomains such as CREBBP, suggesting
their potential to act as generic bromodomain templates. An important
implication is that the bromodomains are not only a phylogenetic family
but also a system in which chemical and structural knowledge of one
bromodomain gives insights transferrable to others
Rapid and Reliable Binding Affinity Prediction of Bromodomain Inhibitors: A Computational Study
Binding
free energies of bromodomain inhibitors are calculated
with recently formulated approaches, namely ESMACS (enhanced sampling
of molecular dynamics with approximation of continuum solvent) and
TIES (thermodynamic integration with enhanced sampling). A set of
compounds is provided by GlaxoSmithKline, which represents a range
of chemical functionality and binding affinities. The predicted binding
free energies exhibit a good Spearman correlation of 0.78 with the
experimental data from the 3-trajectory ESMACS, and an excellent correlation
of 0.92 from the TIES approach where applicable. Given access to suitable
high end computing resources and a high degree of automation, we can
compute individual binding affinities in a few hours with precisions
no greater than 0.2 kcal/mol for TIES, and no larger than 0.34 and
1.71 kcal/mol for the 1- and 3-trajectory ESMACS approaches
Fragment-Based Discovery of Bromodomain Inhibitors Part 2: Optimization of Phenylisoxazole Sulfonamides
Bromodomains are epigenetic reader modules that regulate
gene transcription through their recognition of acetyl-lysine modified
histone tails. Inhibitors of this proteināprotein interaction
have the potential to modulate multiple diseases as demonstrated by
the profound anti-inflammatory and antiproliferative effects of a
recently disclosed class of BET compounds. While these compounds were
discovered using phenotypic assays, here we present a highly efficient
alternative approach to find new chemical templates, exploiting the
abundant structural knowledge that exists for this target class. A
phenyl dimethyl isoxazole chemotype resulting from a focused fragment
screen has been rapidly optimized through structure-based design,
leading to a sulfonamide series showing anti-inflammatory activity
in cellular assays. This proof-of-principle experiment demonstrates
the tractability of the BET family and bromodomain target class to
fragment-based hit discovery and structure-based lead optimization
Discovery of Tetrahydroquinoxalines as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the Second Bromodomain
The bromodomain and extra-terminal
domain (BET) family of proteins
bind acetylated lysine residues on histone proteins. The four BET
bromodomainsīøBRD2, BRD3, BRD4, and BRDTīøeach contain
two bromodomain modules. BET bromodomain inhibition is a potential
therapy for various cancers and immunoinflammatory diseases, but few
reported inhibitors show selectivity within the BET family. Inhibitors
with selectivity for the first or second bromodomain are desired to
aid investigation of the biological function of these domains. Focused
library screening identified a series of tetrahydroquinoxalines with
selectivity for the second bromodomains of the BET family (BD2). Structure-guided
optimization of the template improved potency, selectivity, and physicochemical
properties, culminating in potent BET inhibitors with BD2 selectivity
Discovery of Tetrahydroquinoxalines as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the Second Bromodomain
The bromodomain and extra-terminal
domain (BET) family of proteins
bind acetylated lysine residues on histone proteins. The four BET
bromodomainsīøBRD2, BRD3, BRD4, and BRDTīøeach contain
two bromodomain modules. BET bromodomain inhibition is a potential
therapy for various cancers and immunoinflammatory diseases, but few
reported inhibitors show selectivity within the BET family. Inhibitors
with selectivity for the first or second bromodomain are desired to
aid investigation of the biological function of these domains. Focused
library screening identified a series of tetrahydroquinoxalines with
selectivity for the second bromodomains of the BET family (BD2). Structure-guided
optimization of the template improved potency, selectivity, and physicochemical
properties, culminating in potent BET inhibitors with BD2 selectivity
1,3-Dimethyl Benzimidazolones Are Potent, Selective Inhibitors of the BRPF1 Bromodomain
The
BRPF (bromodomain and PHD finger-containing) protein family are important
scaffolding proteins for assembly of MYST histone acetyltransferase
complexes. Here, we report the discovery, binding mode, and structureāactivity
relationship (SAR) of the first potent, selective series of inhibitors
of the BRPF1 bromodomain
Structure-Based Optimization of Naphthyridones into Potent ATAD2 Bromodomain Inhibitors
ATAD2
is a bromodomain-containing protein whose overexpression is linked
to poor outcomes in a number of different cancer types. To date, no
potent and selective inhibitors of the bromodomain have been reported.
This article describes the structure-based optimization of a series
of naphthyridones from micromolar leads with no selectivity over the
BET bromodomains to inhibitors with sub-100 nM ATAD2 potency and 100-fold
BET selectivity
Discovery of Epigenetic Regulator IāBET762: Lead Optimization to Afford a Clinical Candidate Inhibitor of the BET Bromodomains
The
bromo and extra C-terminal domain (BET) family of bromodomains
are involved in binding epigenetic marks on histone proteins, more
specifically acetylated lysine residues. This paper describes the
discovery and structureāactivity relationships (SAR) of potent
benzodiazepine inhibitors that disrupt the function of the BET family
of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent,
selective compound I-BET762 that is now under evaluation in a phase
I/II clinical trial for nuclear protein in testis (NUT) midline carcinoma
and other cancers
Fragment-Based Discovery of Low-Micromolar ATAD2 Bromodomain Inhibitors
Overexpression of
ATAD2 (ATPase family, AAA domain containing 2)
has been linked to disease severity and progression in a wide range
of cancers, and is implicated in the regulation of several drivers
of cancer growth. Little is known of the dependence of these effects
upon the ATAD2 bromodomain, which has been categorized as among the
least tractable of its class. The absence of any potent, selective
inhibitors limits clear understanding of the therapeutic potential
of the bromodomain. Here, we describe the discovery of a hit from
a fragment-based targeted array. Optimization of this produced the
first known micromolar inhibitors of the ATAD2 bromodomain
The Discovery of IāBET726 (GSK1324726A), a Potent Tetrahydroquinoline ApoA1 Up-Regulator and Selective BET Bromodomain Inhibitor
Through
their function as epigenetic readers of the histone code,
the BET family of bromodomain-containing proteins regulate expression
of multiple genes of therapeutic relevance, including those involved
in tumor cell growth and inflammation. BET bromodomain inhibitors
have profound antiproliferative and anti-inflammatory effects which
translate into efficacy in oncology and inflammation models, and the
first compounds have now progressed into clinical trials. The exciting
biology of the BETs has led to great interest in the discovery of
novel inhibitor classes. Here we describe the identification of a
novel tetrahydroquinoline series through up-regulation of apolipoprotein
A1 and the optimization into potent compounds active in murine models
of septic shock and neuroblastoma. At the molecular level, these effects
are produced by inhibition of BET bromodomains. X-ray crystallography
reveals the interactions explaining the structureāactivity
relationships of binding. The resulting lead molecule, I-BET726, represents
a new, potent, and selective class of tetrahydroquinoline-based BET
inhibitors