Our most recent poll asked how
often synthetic challenges had kept researchers from pursuing a particular
fragment or had impeded a fragment-to-lead project. Around two-thirds replied
sometimes or often. A new open-access paper in Chem. Sci. by Rachel Grainger,
Rhian Holvey, and colleagues at Astex does a deep dive into fragment-to-lead
chemistry, provides a powerful visual tool, and ends with something of a call
to action.
The researchers take as their
starting points 131 fragment-to-lead success stories published from 2015 to
2019 and collated in a series of five J. Med. Chem. Perspectives. All of these started with
fragments (< 300 Da) for which affinity increased by at least 100-fold, with
the resulting leads having affinities of 2 µM or better. As the new paper points
out, this could introduce “survivorship bias,” in that less successful projects
are not included. However, as the point of the paper is to figure out what works,
this likely strengthens the conclusions.
The second observation is that
over 80% of fragments are grown from one or two vectors (examples of one and
two, with the second the subject of the figure above). This is perhaps not
surprising; growing from three or more vectors would likely result in portly
molecules that may be more difficult to advance, venetoclax notwithstanding.
But the really interesting observation
is that the majority of growth vectors (~80%) originate from carbon atoms. Moreover,
more than half of the bonds formed are carbon-carbon bonds. For the non-chemists
in the audience, this is significant because carbon-carbon bond forming
reactions are not always straightforward, particularly in the presence of polar moieties.
In the early days of FBLD, one hope
was that including functional groups such as amides in a fragment collection
would facilitate fragment growing. The new paper suggests that this is naïve: a
functional group in a fragment is likely to interact with the protein and so block
potential growth vectors. Indeed, only 18% of growth vectors come from N-H
groups, despite the fact that these are among the most synthetically accessible.
These findings thus explain why
fragment-to-lead efforts can be so challenging. The researchers provide an
example of a chemical series they ultimately abandoned due to poor synthetic
tractability.
The paper also builds on earlier
papers from Astex exhorting chemists to further advance chemical methodology.
As they conclude:
An “ideal synthesis” of a lead would allow: (1) site-selective formation of bonds at all growing points of a fragment, (2) whilst being mild enough to be compatible with essential polar functionality, and (3) proceeding with minimal or no need for protecting groups….We believe that further development of C-H functionalisation that is tolerant to polar fragments has the potential to transform FBDD.
If you’re in academia, this looks
like a good opening for a grant proposal!
Posts
2 comments:
Thanks Dan for the nice review, which highlights all the key messages we wanted to share with the FBDD and the organic synthesis community. The analysis would not have been possible without all the work you and your co-authors have put into the yearly fragment-to-lead J. Med. Chem. Perspectives.
Hi Marawan,
It's an interesting question, but to paraphrase Chekhov, I suspect the non-analyzed targets are each diverse in their own ways. Our F2L Perspectives note a number of "near misses," and while some fail on the basis of molecular weight, many others fail because the final molecules don't quite cross 2 micromolar, or there is less than 100-fold improvement. In the case of GPCRs in particular, fragment hits can be quite small, as we noted here. I suspect the most frequent challenge is lack of structural information, though as we wrote earlier this year this is not always essential.
Post a Comment