Herein we report the structure-activity and structure-physicochemical
property relationships of a series of class I selective
ortho-aminoanilides targeting the “foot-pocket” in HDAC1&2. To
balance the structural benefits and the physicochemical disadvantages
of these substances, we started with a set of HDACi
related to tacedinaline (CI-994) and evaluated their solubility,
lipophilicity (log D7.4) and inhibition of selected HDAC isoforms.
Subsequently, we selected the most promising “capless” HDACi
and transferred its ZBG to our previously published scaffold
featuring a peptoid-based cap group. The resulting hit compound
10c (LSH-A54) showed favorable physicochemical
properties and is a potent, selective HDAC1/2 inhibitor. The
following evaluation of its slow binding properties revealed
that LSH-A54 binds tightly to HDAC1 in an induced-fit
mechanism. The potent HDAC1/2 inhibitory properties were
reflected by attenuated cell migration in a modified wound
healing assay and reduced cell viability in a clonogenic survival
assay in selected breast cancer cell lines.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:86856 |
| Date | 16 August 2023 |
| Creators | Schäker-Hübner, Linda, Haschemi, Reza, Büch, Thomas, Kraft, Fabian B., Brumme, Birke, Schöler, Andrea, Jenke, Robert, Meiler, Jens, Aigner, Achim, Bendas, Gerd, Hansen, Finn K. |
| Publisher | Wiley-VCH |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | e202100755, 10.1002/cmdc.202100755 |
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