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Design, synthesis and biological evaluation of erlotinib-based IDO1 inhibitors
Xi-Xi Hou1, Xiao-Qing Gong2, Long-Fei Mao1
1The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China.
Abstract:
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 in vitro experiments. Among them, compound 14b (IC50 = 0.59 ± 0.05 μM) had the strongest inhibitory effect on IDO1. In addition, compound 14b significantly inhibited tumor growth comparable to the antitumor activity of erlotinib and the IDO1 inhibitor epacadostat in murine tumor models.
Insights
New erlotinib-based compounds show promise in suppressing indoleamine 2,3-dioxygenase-1 (IDO1) activity. Compound 14b demonstrated significant tumor growth inhibition in preclinical models, suggesting potential for overcoming drug resistance in cancer therapy.
Area of Science:
- Medicinal Chemistry
- Oncology
- Pharmacology
Background:
- Erlotinib is a targeted therapy for non-small-cell lung cancer (NSCLC), but drug resistance limits its efficacy.
- Indoleamine 2,3-dioxygenase-1 (IDO1) is an enzyme implicated in cancer progression and immune evasion.
- Developing novel agents to overcome erlotinib resistance and target IDO1 is crucial for improved cancer treatment.
Purpose of the Study:
- To design and synthesize novel erlotinib-based 1,2,3-triazole compounds.
- To evaluate the inhibitory activity of these compounds against IDO1.
- To assess the in vivo antitumor efficacy of the most potent compounds.
Main Methods:
- Synthesis of erlotinib-based 1,2,3-triazole derivatives.
- In vitro assessment of IDO1 inhibitory activity.
- In vivo evaluation of tumor growth inhibition in murine models.
Main Results:
- Most synthesized compounds exhibited IDO1 inhibitory activity in vitro.
- Compound 14b displayed the most potent IDO1 inhibition (IC50 = 0.59 ± 0.05 μM).
- Compound 14b demonstrated significant tumor growth suppression in vivo, comparable to erlotinib and epacadostat.
Conclusions:
- Erlotinib-based 1,2,3-triazole compounds are effective IDO1 inhibitors.
- Compound 14b shows potential as a novel therapeutic agent for NSCLC, possibly by overcoming erlotinib resistance.
- Further investigation into compound 14b is warranted for its clinical application in cancer therapy.
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