Biomedical Engineering Reference
In-Depth Information
Although not receiving as much attention as protein-protein interactions, tran-
scription factors also play an important role in biological systems, regulating gene
expression based on environmental signals [56]. Like protein-protein interactions,
disruption of protein-DNA interactions could have a tremendous therapeutic benefit,
especially in scenarios of known increased expression having been tied to a disease
pathway. However, for the same reasons as PPIs, transcription factors have largely
not been targeted. Additionally, transcription factor inhibitors must have selective
binding for normal gene expression to occur [57,58]. In this section we describe
recent success in inhibiting both protein-protein and protein-DNA interactions with
compounds derived from DOS libraries. First, we review work done at Infinity Phar-
maceuticals targeting protein-protein interactions involving BCL-2. Second, we look
at a small-molecule library synthesized at the Broad Institute, leading to a selective
inhibitor of the transcription factor HOXA13.
-Cell lymphoma 2 (BCL-2) is a pro-survival protein that is overexpressed in
many types of cancer cells. This increase in protein levels shows that cell survival, as
well as cell proliferation, could be an important role in tumor growth [59,60]. BCL-2
is one of five closely related pro-survival proteins in the mitochondrial pathway for
programmed cell death; BCL-X
L
, BCL-
w
, MCL1, and A1 are the other four proteins
that promote cell life. These pro-survival proteins antagonize two pro-apoptotic pro-
teins, BAX and BAK, which are localized on the mitochondrial outer membrane and
can activate the caspase cascade, and ultimately apoptotic cell death, through release
of cytochrome
c
into the cytosol. Programmed cell death is tightly regulated through
these proteins and is essential for the removal of aged, damaged, or unnecessary cells.
In normal cells, the function of BAX or BAK is suppressed by a pro-survival pro-
tein until an apoptotic signal is received. The conserved BCL-2 homology 3 (BH3)
domain of pro-apoptotic proteins is the primary interaction with pro-survival proteins
responsible for cell survival. In an environment where pro-survival proteins are over-
expressed, disruption of these protein-protein interactions, either by an antagonist
of a pro-survival protein or an agonist of a pro-apoptotic protein, is required for
apoptotic cell death to occur. A limited set of small molecules have shown antagonist
activity against one of the pro-survival proteins in the extended BCL-2 family and
are currently in various stages of clinical trials [59,61].
The first such inhibitors of BCL-2 derived from a DOS strategy were developed
from a diverse library of mono- and bicyclic lactones or the corresponding amide [62].
The synthetic sequence started with a tandem esterification/1,3-dipolar cycloaddition
between allylic alcohol
55
and a nitrono ester using Ti(O
i
-Pr)
4
to give bicyclic lactone
57
(Scheme 17.6). Appendage diversity is built into the library using a variety of
nitrono ester building blocks (ortho, meta, and para substitution on the aryl ring) and
through orthogonal protecting groups on the allylic alcohol, which allows for either
substitution on the lactone or the generation of an exocyclic secondary alcohol. This
approach allowed for the generation of 12 different scaffolds, including enantiomeric
pairs for generation of SSAR. Library production on solid-support lanterns allowed
for further appendage diversity through Sonogashira coupling.
Interestingly, further solid-phase chemistry generated additional skeletal diver-
sity (Scheme 17.7). N-O bond cleavage resulted in monocyclic lactone
59
, while
