Discovery and Optimization of Rationally Designed Bicyclic Inhibitors of Human Arginase to Enhance Cancer Immunotherapy.,ACS Medicinal Chemistry Letters

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Discovery and Optimization of Rationally Designed Bicyclic Inhibitors of Human Arginase to Enhance Cancer Immunotherapy.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-03-23 , DOI: 10.1021/acsmedchemlett.0c00058
Matthew J Mitcheltree ₁ , Derun Li ₁ , Abdelghani Achab ₁ , Adam Beard ₁ , Kalyan Chakravarthy ₁ , Mangeng Cheng ₁ , Hyelim Cho ₁ , Padmanabhan Eangoor ₁ , Peter Fan ₁ , Symon Gathiaka ₁ , Hai-Young Kim ₁ , Charles A Lesburg ₁ , Thomas W Lyons ₁ , Theodore A Martinot ₁ , J Richard Miller ₁ , Spencer McMinn ₁ , Jennifer O'Neil ₁ , Anandan Palani ₁ , Rachel L Palte ₁ , Josep Saurí ₁ , David L Sloman ₁ , Hongjun Zhang ₁ , Jared N Cumming ₁ , Christian Fischer ₁

Affiliation

The action of arginase, a metalloenzyme responsible for the hydrolysis of arginine to urea and ornithine, is hypothesized to suppress immune-cell activity within the tumor microenvironment, and thus its inhibition may constitute a means by which to potentiate the efficacy of immunotherapeutics such as anti-PD-1 checkpoint inhibitors. Taking inspiration from reported enzyme-inhibitor cocrystal structures, we designed and synthesized novel inhibitors of human arginase possessing a fused 5,5-bicyclic ring system. The prototypical member of this class, 3, when dosed orally, successfully demonstrated serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model, despite modest oral bioavailability. Structure-based design strategies to improve the bioavailability of this class, including scaffold modification, fluorination, and installation of active-transport recognition motifs were explored.

中文翻译：

发现和优化合理设计的人精氨酸双环抑制剂以增强癌症免疫治疗。

据推测，精氨酸酶是负责将精氨酸水解为尿素和鸟氨酸的一种金属酶，其作用是抑制肿瘤微环境中的免疫细胞活性，因此其抑制作用可能构成增强免疫治疗功效的手段，例如抗-PD-1检查点抑制剂。从报道的酶抑制剂共晶体结构中汲取灵感，我们设计并合成了具有融合的5,5-双环系统的人类精氨酸酶新型抑制剂。尽管口服生物利用度适中，但该类原型动物3（口服）成功地证明了其在同基因小鼠癌模型中的血清精氨酸酶抑制作用和精氨酸升高。基于结构的设计策略，以改善此类的生物利用度，包括脚手架修改，

更新日期：2020-04-23

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