Paranthaman Priyanga, Karuppasamy Ramanathan, Veerappapillai Shanthi
Department of Biotechnology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India.
Cell Biochem Biophys. 2025 Mar 26. doi: 10.1007/s12013-025-01725-2.
The kynurenine pathway (KP) plays a pivotal role in dampening the immune response in many types of cancer, including TNBC. The intricate involvement of tryptophan degradation via KP serves as a critical regulator in mediating immunosuppression in the tumor microenvironment. The key enzymes that facilitate this mechanism and contribute to tumor progression are indoleamine 2,3-dioxygenase (IDO1) and tryptophan 2,3-dioxygenase (TDO). Despite attempts to use navoximod as a dual-specific inhibitor, its poor bioavailability and lack of clinical efficacy have hampered its utility. To date, no FDA-approved drugs have advanced for dual targeting of these enzymes. Therefore, this study aimed to repurpose the approved drugs from the DrugBank database as novel IDO1/TDO inhibitors. Initially, 2588 FDA-approved compounds were screened by employing molecular docking and pharmacokinetic profiling. Subsequently, methods such as MM-GBSA calculations and machine learning based analysis precisely identified 20 potential lead compounds. The resultant compounds were then assessed for various toxicity endpoints and anticancer activity. The PaccMann server revealed potent anticancer activity, with sensitivities ranging from 0.203 to 24.119 μM against MDA-MB-231 TNBC cell lines. Alongside, the interaction profile with critical residues, strongly reinforced DB06292 (Dapagliflozin) as a compelling hit candidate. Finally, the reliability of the result was corroborated through a rigorous 200 ns molecular dynamics simulation, ensuring the stable binding of the hit against the target proteins. Considering the promising outcomes, we speculate that the proposed hit compound holds strong potential for the management of TNBC.
犬尿氨酸途径（KP）在抑制包括三阴性乳腺癌（TNBC）在内的多种癌症的免疫反应中起着关键作用。通过KP途径进行的色氨酸降解的复杂参与是介导肿瘤微环境中免疫抑制的关键调节因子。促进这一机制并导致肿瘤进展的关键酶是吲哚胺2,3-双加氧酶（IDO1）和色氨酸2,3-双加氧酶（TDO）。尽管尝试将那伏西莫德用作双特异性抑制剂，但其较差的生物利用度和缺乏临床疗效阻碍了其应用。迄今为止，尚无FDA批准的药物用于双重靶向这些酶。因此，本研究旨在将DrugBank数据库中已批准的药物重新用作新型IDO1/TDO抑制剂。最初，通过分子对接和药代动力学分析筛选了2588种FDA批准的化合物。随后，诸如MM-GBSA计算和基于机器学习的分析等方法精确鉴定出20种潜在的先导化合物。然后对所得化合物进行各种毒性终点和抗癌活性评估。PaccMann服务器显示出强大的抗癌活性，对MDA-MB-231 TNBC细胞系的敏感性范围为0.203至24.119μM。与此同时，与关键残基的相互作用图谱有力地强化了DB06292（达格列净）作为一个有吸引力的命中候选物。最后，通过严格的200 ns分子动力学模拟证实了结果的可靠性，确保了命中物与靶蛋白的稳定结合。考虑到这些有前景的结果，我们推测所提出的命中化合物在TNBC的治疗中具有强大的潜力。
