Discovery of Acylsulfonohydrazide-Derived Inhibitors of the Lysine Acetyltransferase, KAT6A, as Potent Senescence-Inducing Anti-Cancer Agents

A high-throughput screen designed
to discover new inhibitors of
histone acetyltransferase KAT6A uncovered CTX-0124143 (1), a unique aryl acylsulfonohydrazide with an IC50 of
1.0 μM. Using this acylsulfonohydrazide as a template, we herein
disclose the results of our extensive structure–activity relationship
investigations, which resulted in the discovery of advanced compounds
such as 55 and 80. These two compounds represent
significant improvements on our recently reported prototypical lead
WM-8014 (3) as they are not only equivalently potent
as inhibitors of KAT6A but are less lipophilic and significantly more
stable to microsomal degradation. Furthermore, during this process,
we discovered a distinct structural subclass that contains key 2-fluorobenzenesulfonyl
and phenylpyridine motifs, culminating in the discovery of WM-1119
(4). This compound is a highly potent KAT6A inhibitor
(IC50 = 6.3 nM; KD = 0.002
μM), competes with Ac-CoA by binding to the Ac-CoA binding site,
and has an oral bioavailability of 56% in rats.