4.2–10-fold BD1 over BD2 selectivity against BRD2, 3, and 4. Further developments with dual kinase/bromodomain inhibitors have been reviewed elsewhere [73].
3.4 Bromodomain Clinical Trials and Chemical Probes
At this point in time, almost half of the 61 bromodomains now have chemical
probes which maintain high selectivity over the majority of other bromodomains
to study their mechanisms of action. Following the first phase I clinical trial in 2012
by GSK of BET inhibitor I-BET/I-BET762/GSK525762 for treating patients with
NUT-midline carcinoma, 26 additional clinical trials are currently underway or have
been either completed or terminated. The most advanced trial, with BET inhibitor,
RVX-208, created by Resverlogix, is in phase III clinical trials for cardiovascular
disease. In all trials, only BET bromodomain inhibitors are under study. Figure 7
summarizes the current status of both clinical trial candidates, and chemical probes
are shown in Fig. 4. These numbers should only grow over time.
4 Part III: Computational and Experimental Biophysical
Methods for Bromodomain Inhibitor Development
4.1 High-Throughput Virtual Screens and Molecular
Dynamic Simulations for Bromodomain Inhibitor
Discovery
Computational methods have been applied to bromodomain ligand discovery
using virtual screening of small molecules against virtual protein structures. This
is enabled by the wealth of bromodomain structures that have been reported as
shown in Table 1. Virtual screening is commonly accomplished using programs
such as Maestro’s Glide docking software, MOE, or more specialized docking
techniques [74–76]. Methods for library selection range from large (millions of
commercially available compounds) available in the ZINC database to focused
libraries based on previously reported scaffolds or drug repurposing of
FDA-approved libraries. Large libraries are useful for discovering previously
unreported pharmacophores for bromodomain inhibition. An example of this is the
discovery of novel scaffolds for BRD4 reported by Vidler et al. [75]. A large virtual
library of compounds was filtered to include pharmacophores similar to the acetylated lysine. Of 2.4 million compounds screened, 240 were taken on for testing in
an AlphaScreen assay, and 6 showed activity against BRD4 BD1. Several of
these molecules were sufficiently soluble and possessed high enough affinity
to be co-crystallized with BRD4 BD1, leading to new substructures for BRD4
inhibitors [75].
306
W. C. K. Pomerantz et al.
3.4 Bromodomain Clinical Trials and Chemical Probes
At this point in time, almost half of the 61 bromodomains now have chemical
probes which maintain high selectivity over the majority of other bromodomains
to study their mechanisms of action. Following the first phase I clinical trial in 2012
by GSK of BET inhibitor I-BET/I-BET762/GSK525762 for treating patients with
NUT-midline carcinoma, 26 additional clinical trials are currently underway or have
been either completed or terminated. The most advanced trial, with BET inhibitor,
RVX-208, created by Resverlogix, is in phase III clinical trials for cardiovascular
disease. In all trials, only BET bromodomain inhibitors are under study. Figure 7
summarizes the current status of both clinical trial candidates, and chemical probes
are shown in Fig. 4. These numbers should only grow over time.
4 Part III: Computational and Experimental Biophysical
Methods for Bromodomain Inhibitor Development
4.1 High-Throughput Virtual Screens and Molecular
Dynamic Simulations for Bromodomain Inhibitor
Discovery
Computational methods have been applied to bromodomain ligand discovery
using virtual screening of small molecules against virtual protein structures. This
is enabled by the wealth of bromodomain structures that have been reported as
shown in Table 1. Virtual screening is commonly accomplished using programs
such as Maestro’s Glide docking software, MOE, or more specialized docking
techniques [74–76]. Methods for library selection range from large (millions of
commercially available compounds) available in the ZINC database to focused
libraries based on previously reported scaffolds or drug repurposing of
FDA-approved libraries. Large libraries are useful for discovering previously
unreported pharmacophores for bromodomain inhibition. An example of this is the
discovery of novel scaffolds for BRD4 reported by Vidler et al. [75]. A large virtual
library of compounds was filtered to include pharmacophores similar to the acetylated lysine. Of 2.4 million compounds screened, 240 were taken on for testing in
an AlphaScreen assay, and 6 showed activity against BRD4 BD1. Several of
these molecules were sufficiently soluble and possessed high enough affinity
to be co-crystallized with BRD4 BD1, leading to new substructures for BRD4
inhibitors [75].
306
W. C. K. Pomerantz et al.