Discovery of a new class of triazole based inhibitors of acetyl transferase KAT2A

Figures & data

Scheme 1. Preparation of triazoles 3 and 4.

Figure 1. Few examples of approved drugs containing a pyridine unit.

Figure 2. Pyridine-based triazoles tested through docking screening against the BioGPS cavity database.

Figure 3. Natural and synthetic HATs inhibitors.

Table 1. Docking scores for triazoles 11–18 found for this dataset of twenty proteins.

Figure 4. PyMOL outlook of triazole 16 bound to KAT2A active site pocket. Triazole’s 16 nitrogens are coloured in blue, carbons in green and oxygens in red.

Table 2. Synthesis of pyridyl-based triazoles 26a-e^a.

Entry	Azide	R	R’	Alkyne	R’’	Product	Yield (%)^b
1	2a	H	H	25a	COOEt	26a	90
2	2a	H	H	25b	(CH2)4COOH	26b	89
3	2b	OCH3	H	25a	COOEt	26c	78
4	2c	H	CH3	25a	COOEt	26d	94
5	2d	H	Cl	25a	COOEt	26e	99

^aReaction conditions: 2a-d (1 equiv.), 25a,b (1.1 equiv.), Cu(OTf)₂*C₆H₅CH₃ (0.1 equiv.), toluene (0.25 M). ^bIsolated yields.

Table 3. Hydrolysis of triazoles 26a,b-d,e to reveal corresponding carboxylates 27a-d^a.

Entry	Triazole	R	R’	Product	Yield (%)^b
1	26a	H	H	27a	87
2	26b	OCH3	H	27b	70
3	26d	H	CH3	27c	71
4	26e	H	Cl	27d	64

^aReaction conditions: 26a,b-d,e (1 equiv.), KOH (1 equiv.), H₂O (1 M).

^bIsolated yields.

Figure 5. KAT2A fluorescence tests performed on triazoles 16, 26c and 27a-d.

Figure 6. MTT assay performed on triazoles 16, 26c and 27a-d. NT = non treated.

Figure 7. WB analysis (on the left) of 16, 26c and 27a-d showing H3K9/14Ac levels in U937 cells following 24 h treatment at the concentration of 200 µM; 5 µM SAHA treatment was used as a positive control of acetylation. Densitometric analysis of WB is shown on the right.