化疗的副作用和药物耐受性的产生仍是它的致命弱点。由于化疗的肿瘤选择性较低和单一的药效密切相关，因此针对肿瘤选择性多功能抗癌剂可能是寻找新的更安全药物的理想策略。在此，我们报道了化合物21的发现。21为1,5-二苯基-3-亚苯基-1H-吡唑啉的硝基取代物，具有双重功能特性。基于2D和3D细胞培养的研究表明，21不仅可以同时诱导EJ28细胞的独立于ROS的凋亡和EGFR/AKT/mTOR介导的自噬性死亡，而且还具有在EJ28球体的增殖区和静止区诱导细胞死亡的能力。分子建模分析表明，21具有EGFR靶向能力，因为它在EGFR活性位点形成稳定的相互作用。结合其在基于斑马鱼的模型中表现出良好的安全性，本研究表明21具有前景，并可能导致肿瘤选择性多功能抗癌剂的发现。版权所有© 2023 Elsevier Masson SAS。保留所有权利。

Unpleasant side effects and resistance development remained the Achilles heel of chemotherapy. Since low tumor-selectivity and monotonous effect of chemotherapy are closely related to such bottleneck, targeting tumor-selective multi-functional anticancer agents may be an ideal strategy in the search of new safer drugs. Herein, we report the discovery of compound 21, a nitro-substituted 1,5-diphenyl-3-styryl-1H-pyrazole that possesses dual functional characteristics. The 2D- and 3D-culture-based studies revealed that 21 not only could induce ROS-independent apoptotic and EGFR/AKT/mTOR-mediated autophagic cell deaths in EJ28 cells simultaneously but also has the ability in inducing cell death at both proliferating and quiescent zones of EJ28 spheroids. The molecular modelling analysis showed that 21 possesses EGFR targeting capability as it forms stable interactions in the EGFR active site. Together with its good safety profile in the zebrafish-based model, the present study showed that 21 is promising and may lead to the discovery of tumor-selective multi-functional anti-cancer agents.Copyright © 2023 Elsevier Masson SAS. All rights reserved.