Discovery of the First Potent IDO1/IDO2 Dual Inhibitors: A Promising Strategy for Cancer Immunotherapy,Journal of Medicinal Chemistry

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Discovery of the First Potent IDO1/IDO2 Dual Inhibitors: A Promising Strategy for Cancer Immunotherapy
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-12-02 , DOI: 10.1021/acs.jmedchem.1c01305
Xin He ₁ , Guangchao He ₁ , Zhaoxing Chu ₂ , Huanhuan Wu ₂ , Junjie Wang ₂ , Yiran Ge ₂ , Hui Shen ₂ , Shan Zhang ₂ , Jinxi Shan ₂ , Kewen Peng ₂ , Zhifeng Wei ₃ , Yi Zou ₁ , Yungen Xu _{1,

2} , Qihua Zhu _{1,

2}

Affiliation

Indoleamine 2,3-dioxygenase-1 (IDO1) plays an important role in tumor immune escape. However, unsatisfactory clinical efficacies of selective IDO1 inhibitors have impeded their further development, suggesting that they do not exert sufficient antitumor effects by selectively inhibiting IDO1. IDO2, an isoenzyme of IDO1, is overexpressed in some human tumors, and emerging evidence suggests that concomitant inhibition of IDO1/2 may have synergistic effects in cancer treatment, revealing a promising cancer immunotherapeutic strategy. Herein, we describe the discovery of compound 4t, the first inhibitor targeting both IDO1/2 that has excellent in vitro inhibitory activity (IDO1 IC₅₀ = 28 nM and IDO2 IC₅₀ = 144 nM). Notably, 4t (TGI = 69.7%) exhibited significantly stronger in vivo antitumor potency than epacadostat (TGI = 49.4%) in CT26 xenograft mouse models, highlighting the advantages of IDO1/2 dual inhibitors for tumor immunotherapy. Preliminary mechanistic studies in vivo further identified that 4t exerts its antitumor effect by inhibiting IDO1/2.

中文翻译：

发现第一个有效的 IDO1/IDO2 双抑制剂：癌症免疫治疗的有希望的策略

Indoleamine 2,3-dioxygenase-1 (IDO1) 在肿瘤免疫逃逸中起重要作用。然而，选择性IDO1抑制剂的临床疗效不理想阻碍了它们的进一步发展，这表明它们不能通过选择性抑制IDO1发挥足够的抗肿瘤作用。IDO2 是 IDO1 的一种同工酶，在一些人类肿瘤中过度表达，新出现的证据表明，伴随抑制 IDO1/2 可能在癌症治疗中具有协同作用，揭示了一种有前途的癌症免疫治疗策略。在此，我们描述了化合物4t的发现，它是第一个靶向 IDO1/2 的抑制剂，具有出色的体外抑制活性（IDO1 IC ₅₀ = 28 nM 和 IDO2 IC ₅₀ = 144 nM）。尤其，在 CT26 异种移植小鼠模型中，4t (TGI = 69.7%) 的体内抗肿瘤效力明显强于epacadostat (TGI = 49.4%)，突出了 IDO1/2 双抑制剂在肿瘤免疫治疗中的优势。体内初步机制研究进一步确定4t通过抑制IDO1/2发挥其抗肿瘤作用。

更新日期：2021-12-23

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