6ye1

Human Ecto-5'-nucleotidase (CD73) in complex with the AMPCP derivative A894 (compound 2n in publication) in the closed form (crystal form IV)

spinqualitylabelsall models 6ye1, resolution 2.66Å 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 2.66Å Ligands: OO2, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Solid tumors are often associated with high levels of extracellular ATP. Ectonucleotidases catalyze the sequential hydrolysis of ATP to adenosine, which potently suppresses T-cell and NK-cell functions via the adenosine receptors (A2a and A2b). The ectonucleotidase CD73 catalyzes the conversion of AMP to adenosine. Thus, increased CD73 enzymatic activity in the tumor microenvironment is a potential mechanism for tumor immune evasion and has been associated with poor prognosis in the clinic. CD73 inhibition is anticipated to restore immune function by skirting this major mechanism of adenosine generation. We have developed a series of potent and selective methylenephosphonic acid CD73 inhibitors via a structure-based design. Key binding interactions of the known inhibitor adenosine-5'-(alpha,beta-methylene)diphosphate (AMPCP) with hCD73 provided the foundation for our early designs. The structure-activity relationship study guided by this structure-based design led to the discovery of 4a, which exhibits excellent potency against CD73, exquisite selectivity against related ectonucleotidases, and a favorable pharmacokinetic profile. Discovery of Potent and Selective Methylenephosphonic Acid CD73 Inhibitors.,Sharif EU, Kalisiak J, Lawson KV, Miles DH, Newcomb E, Lindsey EA, Rosen BR, Debien LPP, Chen A, Zhao X, Young SW, Walker NP, Strater N, Scaletti ER, Jin L, Xu G, Leleti MR, Powers JP J Med Chem. 2021 Jan 14;64(1):845-860. doi: 10.1021/acs.jmedchem.0c01835. Epub, 2021 Jan 5. PMID:33399453 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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