Discovery of Potent and Selective Non-Nucleotide Small Molecule Inhibitors of CD73
Discovery of Potent and Selective Non-Nucleotide Small Molecule Inhibitors of CD73
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DOI：
10.1021/acs.jmedchem.9b01713
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发表时间：
2020-04-23
影响因子：
7.3
通讯作者：
Lawson, Kenneth, V
中科院分区：
文献类型：
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作者：
Beatty, Joel W.;Lindsey, Erick A.;Lawson, Kenneth, V
CD 73是嘌呤能信号传导的细胞外介质。当在肿瘤微环境中上调时，CD 73通过腺苷的过度产生而参与免疫功能的抑制。抑制CD 73的传统努力涉及抗体疗法或小分子的开发，其中最有效的是模拟酶的天然底物腺苷5 '-单磷酸（AMP）的酸性和可电离结构。在这里，我们报告了一种新的非核苷酸类CD 73抑制剂的系统发现，比迄今为止报道的所有其他非膦酸盐抑制剂类更有效。这些努力最终发现了4个（-{5-[4-氟-1-（2 H-吲唑-6-基）-1H-1，2，3-苯并三唑-6-基]-1H-吡唑-1-基}甲基）苯甲腈（73，IC 50 = 12 nM）和4-（{5[4-4-氯-1-（2 H-吲唑-6-基）-1H-1，2，3-苯并三唑-6-基]-1H-吡唑-1-基}甲基）苯甲腈（74，IC 50 = 19 nM）。74与人CD 73的共结合证明了竞争性结合模式。这些化合物显示出通过减弱已知的CD 73核苷抑制剂固有的酸性和低膜渗透性来改善药物样特征的前景。
CD73 is an extracellular mediator of purinergic signaling. When upregulated in the tumor microenvironment, CD73 has been implicated in the inhibition of immune function through overproduction of adenosine. Traditional efforts to inhibit CD73 have involved antibody therapy or the development of small molecules, the most potent of which mimic the acidic and ionizable structure of the enzyme's natural substrate, adenosine 5'-monophosphate (AMP). Here, we report the systematic discovery of a novel class of non-nucleotide CD73 inhibitors that are more potent than all other nonphosphonate inhibitor classes reported to date. These efforts have culminated in the discovery of 4(-{5-[4-fluoro-1-(2H-indazol-6-yl)-1H-1,2,3-benzotriazol-6-yl]-1H-pyrazol-1-yl}methyl)benzonitrile (73, IC50 = 12 nM) and 4-({5[4-4-chloro-1-(2H-indazol-6-yl)-1H-1,2,3-benzotriazol-6-yl]-1H-pyrazol-1-yl}methyl)benzonitrile (74, IC50 = 19 nM). Cocrystallization of 74 with human CD73 demonstrates a competitive binding mode. These compounds show promise for the improvement of drug-like character via the attenuation of the acidity and low membrane permeability inherent to known nucleoside inhibitors of CD73.