title: Design, synthesis, and kinetic characterization of protein N-terminal acetyltransferase inhibitors.
abstract: 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.
authors.affiliation: Department of Molecular Biology, University of Bergen , N-5020 Bergen, Norway.
authors.forename: Håvard
authors.initials: H
authors.lastname: Foyn
authors.forename: Justin E
authors.initials: JE
authors.lastname: Jones
authors.forename: Dan
authors.initials: D
authors.lastname: Lewallen
authors.forename: Rashmi
authors.initials: R
authors.lastname: Narawane
authors.forename: Jan Erik
authors.initials: JE
authors.lastname: Varhaug
authors.forename: Paul R
authors.initials: PR
authors.lastname: Thompson
authors.forename: Thomas
authors.initials: T
authors.lastname: Arnesen
mesh_terms: D000107:Acetylation; D000123:Acetyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000595:Amino Acid Sequence; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D010455:Peptides; D000123:Acetyltransferases; C061313:protein N-terminal acetyltransferase