id	author	title	date	pages	extension	mime	words	sentences	flesch	summary	cache	txt
cord-103271-l9n27ocf	Carozza, Jacqueline A	Structure-aided development of small molecule inhibitors of ENPP1, the extracellular phosphodiesterase of the immunotransmitter cGAMP	2020-05-31		.txt	text/plain	5664	329	51	Cancer cells initiate an innate immune response by synthesizing and exporting the small molecule immunotransmitter cGAMP, which activates the anti-cancer Stimulator of Interferon Genes (STING) pathway in the host. Inspired by the molecular scaffold of a previous inhibitor, QS1, 26, 28 which lacks potency at physiological conditions, we build structure-activity relationships (SAR) around the three sections of the molecule -the zinc-binding head, the core, and the tail -and develop several inhibitors with nanomolar Ki values. Assays used to assess the potency of previously attempted ENPP1 inhibitors are inconsistent 26-34 ; however, developing an appropriate assay is key to determining the utility of the molecules in inhibiting cGAMP degradation under physiological conditions. Since our crystal structure suggests that the zinc-binding phosphonate head and quinazoline tail form the most important interactions with ENPP1, we next sought to explore the core region to achieve optimal geometry between these two functional groups ( Fig. 4a-b) .	./cache/cord-103271-l9n27ocf.txt	./txt/cord-103271-l9n27ocf.txt