The N-termini of 80-90% of human
proteins are acetylated by the
N-terminal acetyltransferases (NATs),
NatA-NatF. The major
NAT complex,
NatA, and particularly the catalytic subunit hNaa10 (ARD1) has been implicated in
cancer development. For example, knockdown of hNaa10 results in
cancer cell death and the arrest of cell proliferation. It also sensitized
cancer cells to drug-induced cytotoxicity. Human NatE has a distinct substrate specificity and is essential for normal chromosome segregation. Thus,
NAT inhibitors may potentially be valuable anticancer
therapeutics, either directly or as adjuvants. Herein, we report the design and synthesis of the first inhibitors targeting these
enzymes. Using the substrate specificity of the
enzymes as a guide, we synthesized three bisubstrate analogues that potently and selectively inhibit the
NatA complex (
CoA-Ac-SES4; IC50 = 15.1 μM), hNaa10, the catalytic subunit of
NatA (
CoA-Ac-EEE4; Ki = 1.6 μM), and NatE/hNaa50 (
CoA-Ac-MLG7; Ki* = 8 nM); CoA-Ac-EEE4 is a reversible competitive inhibitor of hNaa10, and CoA-Ac-MLG7 is a slow tight binding inhibitor of hNaa50. Our demonstration that it is possible to develop
NAT selective inhibitors should assist future efforts to develop
NAT inhibitors with more drug-like properties that can be used to chemically interrogate in vivo
NAT function.