6xue

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

spinqualitylabelsall models 6xue, resolution 1.94Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.94Å Ligands: CA, O1H, PO4, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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-(2H-indazol-6-yl)-1H-1,2,3-benzotriazol-6-yl]-1H-pyrazol-1-yl}m ethyl)benzonitrile (73, IC50 = 12 nM) and 4-({5-[4-chloro-1-(2H-indazol-6-yl)-1H-1,2,3-benzotriazol-6-yl]-1H-pyrazol-1-yl}m ethyl)benzonitrile (74, IC50 = 19 nM). Cocrystallization of 74 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. Discovery of Potent and Selective Non-Nucleotide Small Molecule Inhibitors of CD73.,Beatty JW, Lindsey EA, Thomas-Tran R, Debien L, Mandal D, Jeffrey JL, Tran AT, Fournier J, Jacob SD, Yan X, Drew SL, Ginn E, Chen A, Pham AT, Zhao S, Jin L, Young SW, Walker NP, Leleti MR, Moschutz S, Strater N, Powers JP, Lawson KV J Med Chem. 2020 Apr 8. doi: 10.1021/acs.jmedchem.9b01713. PMID:32212732 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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