Biomedical Engineering Reference
In-Depth Information
HO
Me
OH
N
O
O
Me
N
R 1
N
R
N
R 2
O
H
O
Me
HO
OH
Me
Me
62
micromolar binding affinity to Bcl-2
63
nanomolar binding affinity to Bcl-2
HO
Me
OH
R
O
Me
N
N
N
t -Bu
O
Me
N
Me
Me
Me
64
picomolar binding affinity to Bcl-2
FIGURE 17.13 Discovery of a novel inhibitor of BCL-2 with micromolar binding affinity
from the primary screen using members of the isoxazolidine library. Subsequent optimization
provided a compound with picomolar binding affinity to BCL-2.
amidation of the bi- or monocyclic lactone gave the corresponding mono- or acyclic
amides, respectively. After cleavage from lanterns using HF/pyridine, a total of 20,000
unique compounds were generated for screening in biological assays.
This library was screened for activity against BCL-2 and BCL-xl at Infinity Phar-
maceuticals. Based on a review of the patent [63], the monocyclic isoxazolidine
scaffold showed micromolar binding affinity directly out of the primary screening
deck, a remarkable feat given the limited success with targeting protein-protein inter-
actions. Hits showed that a variety of alkyl alkynes could be used in Sonogashira
cross-coupling, but meta-substitution proved to be critical for activity, showing the
importance of including regioisomers in the original library design ( 62 , Figure 17.13).
The amide also showed that a variety of substituents resulted in activity. However,
the bicyclic lactone showed no activity, illustrating that the amide was necessary for
BCL-2 inhibition. The acyclic amide was also not mentioned, showing the necessity
for the isoxazolidine ring. Another important aspect in the original screen was the
generation of strong SSAR, as the enantiomer of the lead compounds showed no
binding affinity for BCL-2.
Subsequent optimization of the original BCL-2 inhibitor from the isoxazoli-
dine series has resulted in a picomolar binder for BCL-2. Although a variety of
amines can be used to open the lactone and still show activity, the use of (
+
)-
isopinocampheylamine resulted in the strongest activity. Continued optimization of
the aryl substituent resulted in replacing the meta-substituted alkyne with a variety
 
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