Discovery of potent nucleotide pyrophosphatase/phosphodiesterase3 (NPP3) inhibitors with ancillary carbonic anhydrase inhibition for cancer (immuno)therapy.

ABSTRACT: Nucleotide pyrophosphatase/phosphodiesterase3 (NPP3) catalyzes the hydrolysis of extracellular nucleotides. It is expressed by immune cells and some carcinomas, e.g. of kidney and colon. Together with ecto-5'-nucleotidase (CD73), NPP3 produces immunosuppressive, cancer-promoting adenosine, and has therefore been proposed as a target for cancer therapy. Here we report on the discovery of 4-[(4-methylphthalazin-1-yl)amino]benzenesulfonamide (1) as an inhibitor of human NPP3 identified by compound library screening. Subsequent structure-activity relationship (SAR) studies led to the potent competitive NPP3 inhibitor 2-methyl-5-{4-[(4-sulfamoylphenyl)amino]phthalazin-1-yl}benzenesulfonamide (23, K _i 53.7 nM versus the natural substrate ATP). Dockin

SUBMITTER: Lee SY 

PROVIDER: S-EPMC8292979 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature