喉癌是头颈部所有癌症中预后不良的一种，这在临床环境中提出了持续的挑战。连续的NFκB信号通路的过度活化在多种癌症类型中被观察到，包括喉癌。为了开发一种通过NFκB通路靶向喉癌的新药物，我们采用了著名的前导化合物姜黄素，进行了化学修饰，创建了一种称为L42H17的单酮类类似物。该化合物表现出了非凡的稳定性，并显示出对髓样分化蛋白2（MD2）的增强结合亲和力。与预期一致，L42H17表现出了抑制TNF-α诱导的IKK磷酸化、阻止IκB降解以及随后阻断喉癌细胞中NFκB-p65核转位的能力。此外，L42H17还表现出了显著的能力，在不活化cdc2-细胞周期蛋白B1复合物的同时，引发G2-M期细胞周期停滞。此外，它通过减少Bcl-2水平、增加cle-PARP和cle-caspase3的表达来促进细胞凋亡。重要的是，我们观察到L42H17在喉癌患者源性肿瘤异种移植模型中的抗癌功效显著增强。总之，我们的研究结果强烈表明，L42H17有望成为喉癌治疗的潜在候选药物。

Hypopharyngeal carcinoma is notorious for its poor prognosis among all head and neck cancers, posing a persistent challenge in clinical settings. The continuous hyperactivation of the NFκB signaling pathway has been noted in various cancer types, including hypopharyngeal carcinoma. In our quest to develop a novel drug that targets hypopharyngeal cancer via the NFκB pathway, we employed curcumin, a well-known lead compound, and performed chemical modifications to create a mono-carbonyl analog called L42H17. This compound exhibited exceptional stability and displayed an enhanced binding affinity to myeloid differentiation protein 2 (MD2). Consistent with expectations, L42H17 demonstrated the ability to inhibit TNF-α-induced phosphorylation of IKK, prevent IκB degradation, and subsequently impede NFκB-p65 nuclear translocation in hypopharyngeal cancer cells. Additionally, L42H17 exhibited a remarkable capacity to induce cell cycle arrest at the G2-M phase by inactivating the cdc2-cyclin B1 complex. Moreover, it facilitated cell apoptosis by reducing Bcl-2 levels and augmenting the expression of cle-PARP and cle-caspase3. Importantly, we observed a significant enhancement in the anti-cancer efficacy of L42H17 in a patient-derived tumor xenograft (PDTX) model of hypopharyngeal carcinoma. In conclusion, our findings strongly suggest that L42H17 holds promise as a potential candidate drug for the treatment of hypopharyngeal carcinoma in the future.