Fragment growing has been the
dominant strategy of most of the recent posts involving lead optimization,
consistent with our poll results. However, fragment linking can be powerful
too, as illustrated by the recent approval of venetoclax, which was derived
from fragment linking. A recent paper in J.
Med. Chem. by Brad Jordan and colleagues at Amgen provides another nice
case study.
Amgen researchers had previously
used fragment growing to discover inhibitors of BACE1, an Alzheimer’s target
which has been heavily tackled by fragments. However, the most potent molecules
in the series also inhibited the related aspartic protease cathepsin D (CatD),
which could cause serious side effects. The researchers sought to gain
selectivity by building inhibitors to occupy the so-called S3subpocket of BACE1.
To do so, they used 19F-NMR to find fragments that would bind to
BACE1 in the presence of a “blocking compound” that filled most of the active
site but not the S3subpocket. This led to the discovery of seven fragments, the
most potent being compound 3. Interestingly, this fragment only bound in
the presence of the blocking compound as assessed both by NMR and SPR. Also, it
could be competed by a compound that binds in the S3subocket.
Having thus identified a fragment
that bound in the presence of one of their inhibitors, the researchers used
interligand NOE (ILOE) to determine how the two compounds bind relative to one
another. This supported the idea that compound 3 binds in the S3subpocket, and
also suggested how the fragment could be linked onto the existing lead series,
exemplified by compound 5. Just four compounds were designed and synthesized,
and all of them were more potent than either of the starting points, with compound
9 being the best. More importantly, this compound also proved to be ~2000-fold
selective for BACE1 over CatD in enzymatic and cell-based assays.
Despite the excellent (high picomolar)
affinity of compound 9 for BACE1, this is actually about 25-fold worse than
would be predicted by a simplistic additivity of binding energies – a not uncommon occurrence when linking molecules. Still, with its combined used of
multiple NMR techniques and structure-based design to solve a specificity challenge,
this paper is worth perusing.
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