Discovery of a Novel and Selective Indoleamine 2,3-Dioxygenase (IDO-1) Inhibitor 3-(5-Fluoro-1H-indo1-3-yl)pyrrolidine-2,5-dione (EOS200271/PF-06840003) and Its Characterization as a Potential Clinical Candidate
Discovery of a Novel and Selective Indoleamine 2,3-Dioxygenase (IDO-1) Inhibitor 3-(5-Fluoro-1H-indo1-3-yl)pyrrolidine-2,5-dione (EOS200271/PF-06840003) and Its Characterization as a Potential Clinical Candidate
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DOI：
10.1021/acs.jmedchem.7b00974
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发表时间：
2017-12-14
影响因子：
7.3
通讯作者：
Wythes, Martin
中科院分区：
文献类型：
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作者：
Crosignani, Stefano;Bingham, Patrick;Wythes, Martin
肿瘤使用色氨酸分解代谢酶如吲哚胺2,3-双加氧酶（IDO-1）诱导免疫抑制环境。IDO-1在炎症刺激下被诱导，并通过效应t细胞能量和增强Treg功能促进免疫耐受。因此，IDO-1是诱导关键免疫抑制机制的纽带，是肿瘤中重要的免疫治疗靶点。从HTS hit 5开始，IDO-1抑制剂6 （EOS200271/PF-06840003）被开发出来。利用与人IDO-1结合的6的x射线晶体结构描述并合理化了6周围的结构活性关系，表明6与目前描述的大多数IDO-1抑制剂不同，不与血红素铁原子结合，具有新的结合模式。临床候选药物6在IDO-1人全血试验中显示出良好的效力，并且也显示出非常有利的ADME谱，导致良好的预测人药代动力学特性，包括预测的半衰期为16-19小时。
Tumors use tryptophan-catabolizing enzymes such as indoleamine 2,3-dioxygenase (IDO-1) to induce an immunosuppressive environment. IDO-1 is induced in response to inflammatory stimuli and promotes immune tolerance through effector T-cell anergy and enhanced Treg function. As such, IDO-1 is a nexus for the induction of a key immunosuppressive mechanism and represents an important immunotherapeutic target in oncology. Starting from HTS hit 5, IDO-1 inhibitor 6 (EOS200271/PF-06840003) has been developed. The structure activity relationship around 6 is described and rationalized using the X-ray crystal structure of 6 bound to human IDO-1, which shows that 6, differently from most of the IDO-1 inhibitors described so far, does not bind to the heme iron atom and has a novel binding mode. Clinical candidate 6 shows good potency in an IDO-1 human whole blood assay and also shows a very favorable ADME profile leading to favorable predicted human pharmacokinetic properties, including a predicted half-life of 16-19 h.