6YE1

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

6YE1 の概要

• エントリーDOI: 10.2210/pdb6ye1/pdb
• 分子名称: 5'-nucleotidase, ZINC ION, [(2~{R},3~{S},4~{R},5~{R})-5-[2-chloranyl-6-(cyclopentylamino)purin-9-yl]-3,4-bis(oxidanyl)oxolan-2-yl]methoxymethylphosphonic acid, ... (4 entities in total)
• 機能のキーワード: competitive nucleotide inhibitor, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 119710.07

構造登録者

Scaletti, E.,Strater, N. (登録日: 2020-03-23, 公開日: 2021-01-20, 最終更新日: 2024-11-06)

主引用文献

Sharif, E.U.,Kalisiak, J.,Lawson, K.V.,Miles, D.H.,Newcomb, E.,Lindsey, E.A.,Rosen, B.R.,Debien, L.P.P.,Chen, A.,Zhao, X.,Young, S.W.,Walker, N.P.,Strater, N.,Scaletti, E.R.,Jin, L.,Xu, G.,Leleti, M.R.,Powers, J.P.
Discovery of Potent and Selective Methylenephosphonic Acid CD73 Inhibitors.
J.Med.Chem., 64:845-860, 2021

PubMed Abstract: 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 (A and A). 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'-(α,β-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 , which exhibits excellent potency against CD73, exquisite selectivity against related ectonucleotidases, and a favorable pharmacokinetic profile.

PubMed: 33399453
DOI: 10.1021/acs.jmedchem.0c01835

実験手法

X-RAY DIFFRACTION (2.66 Å)