Discovery of Potent and Selective Methylenephosphonic Acid CD73 Inhibitors.
Discovery of Potent and Selective Methylenephosphonic Acid CD73 Inhibitors.
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强效选择性亚甲基膦酸 CD73 抑制剂的发现
DOI：
10.1021/acs.jmedchem.0c01835
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发表时间：
2021
影响因子：
7.3
通讯作者：
Powers JP
中科院分区：
文献类型：
--
作者：
Sharif EU;Kalisiak J;Lawson KV;Miles DH;Newcomb E;Lindsey EA;Rosen BR;Debien LPP;Chen A;Zhao X;Young SW;Walker NP;Sträter N;Scaletti ER;Leleti MR;Powers JP
实体瘤通常与高水平的细胞外ATP相关。外核苷酸酶催化ATP连续水解为腺苷，腺苷通过腺苷受体（A2 a和A2 b）有效抑制T细胞和NK细胞功能。外核苷酸酶CD 73催化AMP转化为腺苷。因此，肿瘤微环境中增加的CD 73酶活性是肿瘤免疫逃避的潜在机制，并与临床预后不良相关。CD 73抑制预期通过避开腺苷生成的这一主要机制来恢复免疫功能。我们已经通过基于结构的设计开发了一系列有效的和选择性的亚甲基膦酸CD 73抑制剂。已知抑制剂腺苷-5 ′-（α，β-亚甲基）二磷酸（AMPCP）与hCD 73的关键结合相互作用为我们的早期设计提供了基础。在基于结构的设计指导下进行的构效关系研究发现了4a，其对CD 73具有优异的效力，对相关的外核苷酸酶具有精确的选择性，并且具有良好的药代动力学特征。
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 (A2aand 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′-(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 of4a, which exhibits excellent potency against CD73, exquisite selectivity against related ectonucleotidases, and a favorable pharmacokinetic profile.