6Z9B
Human Ecto-5'-nucleotidase (CD73) in complex with AOPCP derivative A830 (compound 16 in publication) in the closed form (crystal form III)
Summary for 6Z9B
| Entry DOI | 10.2210/pdb6z9b/pdb |
| Descriptor | 5'-nucleotidase, ZINC ION, CALCIUM ION, ... (5 entities in total) |
| Functional Keywords | zinc enzyme, nucleotide analog, inhibitor, arcus biosciences, hydrolase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 59983.09 |
| Authors | Strater, N.,Scaletti, E. (deposition date: 2020-06-03, release date: 2020-07-22, Last modification date: 2024-10-16) |
| Primary citation | Lawson, K.V.,Kalisiak, J.,Lindsey, E.A.,Newcomb, E.T.,Leleti, M.R.,Debien, L.,Rosen, B.R.,Miles, D.H.,Sharif, E.U.,Jeffrey, J.L.,Tan, J.B.L.,Chen, A.,Zhao, S.,Xu, G.,Fu, L.,Jin, L.,Park, T.W.,Berry, W.,Moschutz, S.,Scaletti, E.,Strater, N.,Walker, N.P.,Young, S.W.,Walters, M.J.,Schindler, U.,Powers, J.P. Discovery of AB680: A Potent and Selective Inhibitor of CD73. J.Med.Chem., 63:11448-11468, 2020 Cited by PubMed Abstract: 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 ( = 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. PubMed: 32614585DOI: 10.1021/acs.jmedchem.0c00525 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.17 Å) |
Structure validation
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