HAT Inhibitors

The HDACi s mentioned above inhibit exclusively Zn2+-dependent HDACs and not the NAD-dependent Sittuins. Researcher also focuses on development of sirtunin inhibitors and first successes like the compound siitinol have been repotted. Finally, the development of HAT inhibitors is also pursued and to date some compounds like the peptide-based inhibitor H3-CoA-20 or the small molecule MB-3 are among the first molecules to show HAT inhibition [3]. 

Several small molecule modulators (SMM) of p300 and PCAF have been developed (Varier et al, 2004). Recently, the first naturally occurring HAT inhibitor anacardic acid was isolated from cashew nut shell liquid, which inhibits the HAT activity of both p300 and PCAF very effectively (Balasubramanyam et al, 2003). By using anacardic acid as a synthon, an amide derivative of anacardic acid, CTPB, has been synthesized, which is the only known small molecule activator of any histone acetyltransferase, in this case, p300. However, cells are impermeable or... 

Further HAT inhibitors are the naturally occurring compounds curcumin 14 and garcinol IS (Figure 11.4). They show equal activity in vitro and in vivo. 

Among the histone modifying enzymes, HATs and HDACs are the best characterized biochemically and provide attractive opportunities for interdisciplinary research between chemists and biologists. At present, the HDACs have outstripped the HATs in terms of their impact on drug discovery. Multiple HDAC inhibitors from several chemical classes are currently in clinical trials for cancer chemotherapy, whereas the literature on HAT inhibitors is limited to in vitro data. 

Another report showed curcumin (a component of many tropical spices) as a novel histone acetyl transferase (HAT) inhibitor [53]. The report showed that curcumin could block acetylation of histone and p53 in vivo, which led to apoptosis of Hela cells. Therefore, potential in the future exists to develop HAT inhibitors for managing cancers. 

---