6XUE

Human Ecto-5'-nucleotidase (CD73) in complex with A2396 (compound 74 in publication) in the closed form in crystal form IV

Summary for 6XUE

• Entry DOI: 10.2210/pdb6xue/pdb
• Descriptor: 5'-nucleotidase, ZINC ION, CALCIUM ION, ... (6 entities in total)
• Functional Keywords: non-nucleotide inhibitor, hydrolase, arcus biosciences
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 120322.45

Authors

Strater, N. (deposition date: 2020-01-19, release date: 2020-04-22, Last modification date: 2024-10-23)

Primary citation

Beatty, J.W.,Lindsey, E.A.,Thomas-Tran, R.,Debien, L.,Mandal, D.,Jeffrey, J.L.,Tran, A.T.,Fournier, J.,Jacob, S.D.,Yan, X.,Drew, S.L.,Ginn, E.,Chen, A.,Pham, A.T.,Zhao, S.,Jin, L.,Young, S.W.,Walker, N.P.,Leleti, M.R.,Moschutz, S.,Strater, N.,Powers, J.P.,Lawson, K.V.
Discovery of Potent and Selective Non-Nucleotide Small Molecule Inhibitors of CD73.
J.Med.Chem., 63:3935-3955, 2020

PubMed Abstract: CD73 is an extracellular mediator of purinergic signaling. When upregulated in the tumor microenvironment, CD73 has been implicated in the inhibition of immune function through overproduction of adenosine. Traditional efforts to inhibit CD73 have involved antibody therapy or the development of small molecules, the most potent of which mimic the acidic and ionizable structure of the enzyme's natural substrate, adenosine 5'-monophosphate (AMP). Here, we report the systematic discovery of a novel class of non-nucleotide CD73 inhibitors that are more potent than all other nonphosphonate inhibitor classes reported to date. These efforts have culminated in the discovery of 4-({5-[4-fluoro-1-(2-indazol-6-yl)-1-1,2,3-benzotriazol-6-yl]-1-pyrazol-1-yl}methyl)benzonitrile (, IC = 12 nM) and 4-({5-[4-chloro-1-(2-indazol-6-yl)-1-1,2,3-benzotriazol-6-yl]-1-pyrazol-1-yl}methyl)benzonitrile (, IC = 19 nM). Cocrystallization of with human CD73 demonstrates a competitive binding mode. These compounds show promise for the improvement of drug-like character via the attenuation of the acidity and low membrane permeability inherent to known nucleoside inhibitors of CD73.

PubMed: 32212732
DOI: 10.1021/acs.jmedchem.9b01713

Experimental method

X-RAY DIFFRACTION (1.94 Å)