Dipartimento Neurofarba, Sezione Di Scienze Farmaceutiche E Nutraceutiche, Università Degli Studi Di Firenze, Sesto Fiorentino (Florence), Italy.
Department of Biology, Agriculture and Food Sciences, CNR, Institute of Biosciences and Bioresources, Napoli, Italy.
Expert Opin Ther Pat. 2021 Oct;31(10):867-876. doi: 10.1080/13543776.2021.1923694. Epub 2021 May 13.
Hydrolysis of AMP to adenosine and inorganic phosphate is catalyzed by 5´-ectonucleotidase, e5NT, alias CD73, a metalloenzyme incorporating two zinc ions at its active site. e5NT is involved in crucial physiological and pathological processes, such as immune ho meostasis, inflammation, and tumor progression. CD73 inhibitors belonging to the monoclonal antibodies (MAbs) and small molecules started to be considered as candidates for the immunotherapy of tumors.
We review the drug design landscape in the scientific and patent literature on CD73 inhibitors from 2017 to the present. Small-molecule inhibitors were mostly discussed, although the MAbs are also considered.
Considerable advances have been reported in the design of nucleotide/nucleoside-based CD73 inhibitors, after the X-ray crystal structure of the enzyme in complex with the non-hydrolyzable ADP analog, adenosine (α,β)-methylene diphosphate (AMPCP), was reported. A large number of highly effective such inhibitors are now available, through modifications of the nucleobase, sugar and zinc-binding groups of the lead. Few classes of non-nucleotide inhibitors were also reported, including flavones, anthraquinone ssulfonates, and primary sulfonamides. A highly potent ssmall-molecule CD73 inhibitor, AB680, is presently in the early phase of clinical trials as immunotherapeutic agents against various types of cancer.
AMP 水解为腺苷和无机磷酸盐由 5´-核苷酸酶（e5NT），又名 CD73，一种在其活性位点包含两个锌离子的金属酶催化。e5NT 参与免疫稳态、炎症和肿瘤进展等关键生理和病理过程。属于单克隆抗体（MAb）和小分子的 CD73 抑制剂开始被认为是肿瘤免疫治疗的候选药物。
我们综述了 2017 年至今科学文献和专利文献中 CD73 抑制剂的药物设计概况。主要讨论了小分子抑制剂，尽管也考虑了 MAb。
在报道了酶与非水解 ADP 类似物腺苷（α，β）-亚甲基二磷酸（AMPCP）复合物的 X 射线晶体结构后，报道了核苷酸/核苷基 CD73 抑制剂设计的相当大的进展。现在，通过对先导物的核碱基、糖和锌结合基团的修饰，得到了大量高效的此类抑制剂。还报道了包括黄酮类、蒽醌磺酸盐和初级磺酰胺在内的几类非核苷酸抑制剂。一种高效的小分子 CD73 抑制剂 AB680 目前正在临床试验的早期阶段，作为针对各种类型癌症的免疫治疗药物。
