ACY-738

ACY-738 is a very potent HDAC6 inhibitor (IC₅₀ of 1.7 nM) with >50-100X selectivity against other HDAC isoforms. It has poor PK, and thus has to be administered by either IV or IP routes. Calculated physicochemical properties: MW 270.3, PSA 87.1, AlogP 1.32, clogD pH 7 1.28, HBDon 3 (in water 2 since the hydroxamic acid is highly ionized), HBAcc 5, Nrot 4, Ligand Efficiency (LE) 0.588, Lipophilicity Ligand Efficiency (LipE) 7.49. Although quite a few HDAC inhibitors have been approved as drugs and more are in clinical trials (Vorinostat, Panobinostat, Entinostat, Mocetinostat, Belinistat, Quisinostat, Chidamide, Abexinostat, ACY-1215), ACY-738 seems to be the only >50-100X selective HDAC6 inhibitor (against other 10 HDACs). Despite the fact that it has poor PK and it as to be administered either IV or IP (plasma half-life of 0.2 h), it showed good brain-to-plasma ratio of 1.22. Thus it can be used to tease out the role of HDAC6 in brain for the prevention (and hopefully for the treatment) of Alzheimer’s and development of novel first-in-class antidepressants. The lower level for cell potency is not clear: only 2.5 uM was reported. The probe needs to be profiled over a large panel of cell lines to have a better understanding of the cellular doses as well as applicability. Several crystal structures of HDAC6 catalytic domain 2 are available in RCSB with approved drugs and other similar compounds. Thus, this chemical probe can be improved in terms of in vivo exposure, half-life, and route of administration, while capitalizing on HDAC selectivity and brain exposure.

While this probe is highly potent for the intended target in vitro, the cellular potency is not discerned as these experiments were only carried out at a single dose (2.5 microM). I would like to see cellular experiments performed at lower doses in order to assess the cellular potency of this compound. In addition, because of the chemical nature of this compound, off-target selectivity on other epigenetic targets in addition to GPCRs and kinases would enhance its value. For the animal studies in wild-type and knockout backgrounds, it would be useful to know the absolute levels of tubulin acetylation (as opposed to relative to vehicle). This will enable a comparison of the wild-type-treated response relative to the knockout baseline.