6z9b

Human Ecto-5'-nucleotidase (CD73) in complex with AOPCP derivative A830 (compound 16 in publication) in the closed form (crystal form III)

spinqualitylabelsall models 6z9b, resolution 2.17Å 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 2.17Å Ligands: CA, QCQ, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Extracellular adenosine (ADO), present in high concentrations in the tumor microenvironment (TME), suppresses immune function via inhibition of T cell and NK cell activation. Intratumoral generation of ADO depends on the sequential catabolism of ATP by two ecto-nucleotidases, CD39 (ATP --> AMP) and CD73 (AMP --> ADO). Inhibition of CD73 eliminates a major pathway of ADO production in the TME and can reverse ADO-mediated immune suppression. Extensive interrogation of structure-activity relationships (SARs), structure-based drug design, and optimization of pharmacokinetic properties culminated in the discovery of AB680, a highly potent (Ki = 5 pM), reversible, and selective inhibitor of CD73. AB680 is further characterized by very low clearance and long half-lives across preclinical species, resulting in a PK profile suitable for long-acting parenteral administration. AB680 is currently being evaluated in phase 1 clinical trials. Initial data show AB680 is well tolerated and exhibits a pharmacokinetic profile suitable for biweekly (Q2W) iv-administration in human. Discovery of AB680: A Potent and Selective Inhibitor of CD73.,Lawson KV, Kalisiak J, Lindsey EA, Newcomb ET, Leleti MR, Debien L, Rosen BR, Miles DH, Sharif EU, Jeffrey JL, Tan JBL, Chen A, Zhao S, Xu G, Fu L, Jin L, Park TW, Berry W, Moschutz S, Scaletti E, Strater N, Walker NP, Young SW, Walters MJ, Schindler U, Powers JP J Med Chem. 2020 Jul 20. doi: 10.1021/acs.jmedchem.0c00525. PMID:32614585 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA