Background:

IC50: 100 μM

Butyrolactone 3 is a histone acetyltransferase Gcn5 inhibitor.

The human histone acetyltransferase Gcn5 is identified as a prominent member of the GNAT family with high preference for histone H3 as a substrate.

In vitro: The analogs of butyrolactone 3 only showed a weak inhibition of CBP, while butyrolactone 3 led to an inhibition of Gcn5. It was important to see that in the presence of acetyl-CoA the Kd value for binding of histone H3 to Gcn5 or PCAF was around 100 mM. Moreover, the affinity of butyrolactone 3 to the Gcn5 enzyme was found to be comparable to that of the natural substrate H3 and could provide an good starting point for the study of SAR. In addition, a nonirreversible inhibition of Gcn5 could be determine, and thus a Michael addition of nucleophilic groups of the enzymeBs active side was unlikely. Therefore, the derivatization of gbutyrolactone 3 at position 2 might be a promising starting point for future SAR studies [1].

In vivo: So far, there is no animal in vivo data reported.

Clinical trial: Up to now, Butyrolactone 3 is still in the preclinical development stage.

Reference:
1.  M. Biel, A. Kretsovali, E. Karatzali, et al. Design, synthesis, and biological evaluation of a small-molecule inhibitor of the histone acetyltransferase Gcn5. Angewandte Chemie International Edition 43, 3974-3976 (2004).