Histone deacetylases (HDACs) are epigenetic writers that –
as their name suggests – remove acetyl groups from lysine residues in histones.
They have been pursued as anticancer targets for decades; vorinostat was
approved back in 2006 (and arguably has fragment origins). The catalytic site
of HDACs contains a zinc ion, and many inhibitors include zinc-binding moieties,
often hydroxamic acids. However, the high affinity of these metallophilic
fragments leads to inhibition of other zinc-containing enzymes, causing
toxicity. In a new ACS Med. Chem. Lett. paper, Emiliano Tamanini, Shin
Miyamura, and colleagues at Astex and Otsuka provide alternative chemistries.
(Emiliano presented part of this story at Pacifichem last year.)
The researchers were specifically interested in HDAC2, which
has been implicated in neurodegenerative diseases such as Alzheimer’s. Because
of the chronic nature of these conditions, selectivity was all the more
important, as was brain penetration. Screens of the Astex fragment library,
along with a set of known zinc-binding fragments, yielded 35
crystallographically validated hits. These included compound 3, which forms
bidentate interactions with the catalytic zinc through the amine and carbonyl
moieties.
An additional fragment (compound 4, not shown) bound in a
pocket at the “foot” of the catalytic site, which is normally partially blocked
by a side chain residue. Yet another fragment bound near the entrance tunnel.
Growing compound 3 in both directions led to compound 7, the first molecule of
the series with measurable activity in a fluorescence assay. Rigidification and
further growing led to compound 9, with low micromolar activity.
Interestingly, merging compound 9 directly with foot-pocket
binder compound 4 did not improve activity, but adding a chlorine atom to fill
a small subpocket increased affinity two-fold (compound 13). Finally, optimization
of the moiety at the entrance tunnel (the isoindoline of compound 13) yielded compound 17, with high nanomolar
potency.
Compound 17 caused increased acetylation of H4K12 in cells.
More importantly, it showed good brain exposure when orally dosed in mice, and
H4K12 acetylation was observed in mouse brain tissue. The compound hits HDAC1
and HDAC8 with similar potency as HDAC2, and these could be contributing to the
biological effect. Nonetheless, while potency and selectivity still need to be
improved, compound 17 is an attractive lead for further optimization.
In a comment to the Notum work we highlighted back in May,
Daniel Beck wondered whether “fragments are especially good starting points for
CNS target campaigns.” This paper suggests the answer is yes.
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