Five years ago Teddy highlighted a paper from
GlaxoSmithKline that reported the discovery and characterization of several
different fragments that bind to members of the BET family of bromodomains,
epigenetic readers that recognize acetylated lysine residues in histones. Researchers
at FORMA were among those paying attention to these developments. David Millan
and his colleagues have now published in ACS
Med. Chem. Lett. their account of how they were able to advance one of
these fragments to a chemical probe.
As the researchers note, many different BET inhibitors have
been reported; we discussed two separate series just a few months ago.
Chemical novelty was thus a challenge, particularly as they were starting with
a fragment (compound 1) reported by a large company. They thus chose to tweak
the fragment slightly to intermediate 2. Importantly, introduction of the second
nitrogen also introduces another synthetic vector with potential to pick up
interactions with the so-called “WPF shelf”. This explicit consideration of
synthetic tractability in fragment design enables rapid progress.
Parallel chemistry led to compound 6, with measurable biochemical
activity against BRD4. Further growing from the phenyl ring led to compound 8,
with sub-micromolar biochemical and antiproliferative activity. A crystal
structure revealed that the newly introduced amide functionality was pointed
toward solvent, which would allow modulation of the physicochemical properties.
More medicinal chemistry followed, with considerable effort
on improving the plasma and liver microsome stability. This campaign involved a
combination of rational design and parallel synthesis along with a keen focus
on minimizing lipophilicity. Ultimately the researchers arrived at FT001, with
good activity and stability. This compound was also selective for BET family
members over other bromodomains and displayed reasonable pharmacokinetics and
impressive activity in a mouse xenograft model.
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