Comparative Analysis of Drug-like EP300/CREBBP Acetyltransferase Inhibitors

The
human acetyltransferase paralogues EP300 and CREBBP are master
regulators of lysine acetylation whose activity has been implicated
in various cancers. In the half-decade since the first drug-like inhibitors
of these proteins were reported, three unique molecular scaffolds
have taken precedent: an indane spiro-oxazolidinedione (A-485), a
spiro-hydantoin (iP300w), and an aminopyridine (CPI-1612). Despite
increasing use of these molecules to study lysine acetylation, the
dearth of data regarding their relative biochemical and biological
potencies makes their application as chemical probes a challenge.
To address this gap, here we present a comparative study of drug-like
EP300/CREBBP acetyltransferase inhibitors. First, we determine the
biochemical and biological potencies of A-485, iP300w, and CPI-1612,
highlighting the increased potencies of the latter two compounds at
physiological acetyl-CoA concentrations. Cellular evaluation shows
that inhibition of histone acetylation and cell growth closely aligns
with the biochemical potencies of these molecules, consistent with
an on-target mechanism. Finally, we demonstrate the utility of comparative
pharmacology by using it to investigate the hypothesis that increased
CoA synthesis caused by knockout of PANK4 can competitively antagonize
the binding of EP300/CREBBP inhibitors and demonstrate proof-of-concept
photorelease of a potent inhibitor molecule. Overall, our study demonstrates
how knowledge of the relative inhibitor potency can guide the study
of EP300/CREBBP-dependent mechanisms and suggests new approaches to
target delivery, thus broadening the therapeutic window of these preclinical
epigenetic drug candidates.