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Selective HDAC4 inhibitors as potential therapeutics for Huntington's disease (M155)
Cronk D, Aziz O, Vann J, Pett H, Wong M, Gowers I, Martin R, McAllister G, Thomas E, Stott A, Haughan A, Stones L, Vater H, Wall M, Allen D, Breccia P, Raphy G, Richardson C, Matthews K, Yates D, Kiselyov A, Bard J, Beconi M, Beaumont V, Dominguez C, Munoz Sanjuan I, Burli R.
Huntington’s disease (HD) is a genetic, neurodegenerative disorder that causes abnormal muscle coordination and leads to cognitive decline and dementia. HDAC4 is one of eleven metal-dependent histone deacetylase isoforms (HDACs) that has been recognized as a potential target for HD, based on the finding that the heterozygous knock down of the HDAC4 gene in R6/2 mice (disease model) resulted in a partially restored phenotype (personal communication, Professor Gill Bates, King’s College London). As HDAC4 adopts multiple biological functions, a critical question is whether blockage of its catalytic site will replicate the knockdown data. To determine this, our objective is to develop potent and selective HDAC4 deacetylase inhibitors that exhibit pharmacokinetic profiles suitable for a proof-of-concept study in R6/2 mice. We have assessed HDAC activity in Jurkat E6.1 cells utilizing two assays that target class I and class II HDAC enzymes through the use of two different substrates, Boc-Lys(Ac)-AMC and Boc-Lys(TFA)-AMC. Removal of the acetyl (Ac) or the trifluoro-acetyl (TFA) groups, by deacetylase enzymes, allows the liberation of the AMC group by trypsin, which is fluorescent once separated from the Boc group of the substrates. This method has been adapted to allow the measurement of HDAC activity in isolated enzymes, including the catalytic domain of HDAC4. Using these biological and a panel of ADME assays, compounds have been screened and improved through an iterative process. Several molecules with promising HDAC4 inhibitory activity (selective for Class IIa), good stability in the presence of liver microsomes and little potential for Pgp-mediated efflux have been identified.
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