Early Drug‐Discovery Efforts towards the Identification of EP300/CBP Histone Acetyltransferase (HAT) Inhibitors

Abstract

EP300 and CBP (KAT3A/3B) are two highly homologous, multidomain, epigenetic coregulators that play central roles in transcription through the acetylation of lysine residues on histones and other proteins. Both enzymes have been implicated in human diseases, especially cancer. From a high‐throughput screen of 191 000 compounds searching for EP300/CBP histone acetyltransferase (HAT) inhibitors, 18 compounds were characterized by a suite of biochemical enzymatic assays and biophysical methods, including X‐ray crystallography and native mass spectrometry. This work resulted in the discovery of three distinct mechanistic classes of EP300/CBP HAT inhibitors, including two classes not previously described. The profiles of an example of each class of inhibitor are described in detail. A subsequent medicinal chemistry effort led to the development of a novel class of orally bioavailable AcCoA‐competitive EP300/CBP HAT inhibitors with in vivo activity. We believe that this work will prove to be a useful guide for other groups interested in the development of HAT inhibitors.

Comparative Analysis of Drug-like EP300/CREBBP Acetyltransferase Inhibitors

“…A unifying aspect of EP300/CREBBP probes 1 – 3 is that they are all acetyl-CoA competitive. A competitive mechanism is unambiguously supported by kinetic studies of 1 and is inferred for 2 and 3 based on similarities in chemical structure, biochemical screening data, and overlap with the acetyl-CoA binding site in crystallographic studies . Due to this, their inhibition is expected to scale linearly with the amount of cofactor present in the enzyme reaction.…”

An insight into therapeutic efficacy of heterocycles as histone‐modifying enzyme inhibitors that targets cancer epigenetic pathways

“…Further, their search led to the development of two compounds ( 18 , ) as Acetyl‐CoA competitive EP300/CBP HAT inhibitors with in vivo activity with IC50 values of 2.5 μM and 9 nM. (Huhn et al, 2020).…”

“…Further, their search led to the development of two compounds (18, ) as Acetyl-CoA competitive EP300/CBP HAT inhibitors with in vivo activity with IC50 values of 2.5 μM and 9 nM. (Huhn et al, 2020). | 691 inhibitor H 4 K 12 CoA (20) has shown a low K i value of 1.1 nM for HAT1, compare to both Acetyl-CoA and H4 peptide (Ngo et al, 2019) [Figure 5].…”

Synthesis and Biological Evaluation of Spirocyclic Chromane Derivatives as a Potential Treatment of Prostate Cancer

“…On the basis of A-485, Zhou et al identified a preclinical candidate B026 (5) with excellent pharmacological properties with the assistance of artificial intelligence and further optimization [26]. In the past decade, several other HAT inhibitors 6-8 with excellent potency have been reported [27][28][29][30][31]. A-485 represents a significant breakthrough, but the cell potency still requires improvement.…”