Hou Xi-Xi, Gong Xiao-Qing, Mao Long-Fei, Sun Ge, Yang Jian-Xue
The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China.
College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, China.
Front Pharmacol. 2022 Aug 10;13:940704. doi: 10.3389/fphar.2022.940704. eCollection 2022.
Erlotinib is a highly specific and reversible epidermal growth factor receptor tyrosine kinase inhibitor for the targeted therapy of non-small-cell lung cancer (NSCLC) However, the efficacy of erlotinib is limited because the development of drug resistance during chemotherapy. Indoleamine 2,3-dioxygenase-1 (IDO1) is a rate-limiting tryptophan catabolic enzyme that is activated in many human cancers. In this study, we designed a series of erlotinib-based 1,2,3-triazole compounds by combining erlotinib with phenyl or benzyl azide. Attentive FP prediction model was used to predict the bioactivity of those compounds. We discovered that most of the erlotinib-based 1,2,3-triazole compounds are capable of suppressing IDO1 activities experiments. Among them, compound (IC = 0.59 ± 0.05 μM) had the strongest inhibitory effect on IDO1. In addition, compound significantly inhibited tumor growth comparable to the antitumor activity of erlotinib and the IDO1 inhibitor epacadostat in murine tumor models.
厄洛替尼是一种高度特异性且可逆的表皮生长因子受体酪氨酸激酶抑制剂，用于非小细胞肺癌（NSCLC）的靶向治疗。然而，厄洛替尼的疗效有限，因为化疗期间会产生耐药性。吲哚胺2,3-双加氧酶-1（IDO1）是一种在许多人类癌症中被激活的色氨酸分解代谢限速酶。在本研究中，我们通过将厄洛替尼与苯基或苄基叠氮化物结合，设计了一系列基于厄洛替尼的1,2,3-三唑化合物。使用精心构建的FP预测模型来预测这些化合物的生物活性。我们发现，大多数基于厄洛替尼的1,2,3-三唑化合物在实验中能够抑制IDO1活性。其中，化合物（IC = 0.59 ± 0.05 μM）对IDO1的抑制作用最强。此外，在小鼠肿瘤模型中，化合物对肿瘤生长的抑制作用与厄洛替尼和IDO1抑制剂依帕司他的抗肿瘤活性相当。
