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Daniela Danková @danieladankova.bsky.social · 13/12/2024

Finally, @tnhansen.bsky.social tested the macrocycle for the downstream effects of HDAC11 inhibition. YAP1 and SOX2, which are both regulated by HDAC11, were significantly depleted following the treatment with the macrocycles.

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Daniela Danková @danieladankova.bsky.social · 13/12/2024

We next turned the macrocycle into a cell permeability probe by a single atom H --> Cl change on the N-hexyl Asuha. It was then employed in chloroalkane penetration assay by Christian Bartling from the Strømgaard lab. The data shows that the macrocycle is highly cell penetrable with CP50 of 43nM.

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Daniela Danková @danieladankova.bsky.social · 13/12/2024

Excitingly, the macrocycles inhibit demyristoylation, but not deacetylation in HDAC11-expressing breast cancer cell lysates. Marie Hesse, a great MSc student, then turned the inhibitor into a pulldown probe and succeeded at pulling down HDAC11 together with its only known interaction partner HDAC6.

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Daniela Danková @danieladankova.bsky.social · 13/12/2024

Through SAR study on the zinc-binding moiety, we confirmed it was the N-alkylation that was driving the selectivity towards HDAC11 , as the non-alkylated analogue was a potent broad-spectrum HDAC inhibitor. Meanwhile, C6 and C14 analogues showed minimal activity against remaining 10 HDAC isozymes.

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Daniela Danková @danieladankova.bsky.social · 13/12/2024

Somewhat surprisingly, considering all compounds contained a zinc-binding group, only 12 HDAC11 inhibitors (out of 4608!) were identified in the screening. 7 hits were resynthesized and 6/7 showed selectivity for HDAC11 over HDAC1. Our lead 420-L4, in particular, showed high potency (Ki of 40nM).

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Daniela Danková @danieladankova.bsky.social · 13/12/2024

@alexanderln.bsky.social, a former colleague from @ucph.bsky.social and then a postdoc in the Heinis lab synthesized and screened the library, employing their state-of-art automated and high-throughput SPPS and macrocyclization: doi.org/10.1002/anie...

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Daniela Danková @danieladankova.bsky.social · 13/12/2024

Inspired by natural product(like) macrocyclic inhibitors of class I HDACs, we aimed to discover HDAC11-selective macrocyclic inhibitors. We designed a biased peptide macrocyclic library (>4600 members) carrying N-alkylated hydroxamic acid moiety to mimic the natural substrate of HDAC11.

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