Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, ENSCM, Université de Montpellier, 34090 Montpellier, France.
Department of Biology, Faculty of Sciences, GSBT Laboratory, Lebanese University, R. Hariri Campus, Hadath 1533, Lebanon.
Int J Mol Sci. 2024 Jul 16;25(14):7785. doi: 10.3390/ijms25147785.
Imiqualines are analogues of the immunomodulatory drug imiquimod. EAPB02303, the lead of the second-generation imiqualines, is characterized by significant anti-tumor effects with IC50s in the nanomolar range. We used transgenic and mutant strains of two key signaling pathways (PI3K-Akt and Ras-MAPK) disrupted in human cancers to investigate the mode of action of EAPB02303. The ability of this imiqualine to inhibit the insulin/IGF1 signaling (IIS) pathway via the PI3K-Akt kinase cascade was explored through assessing the lifespan of wild-type worms. Micromolar doses of EAPB02303 significantly enhanced longevity of N2 strain and led to the nuclear translocation and subsequent activation of transcription factor DAF-16, the only forkhead box transcription factor class O (Fox O) homolog in . Moreover, EAPB02303 significantly reduced the multivulva phenotype in /Ras mutant strains MT2124 and MT4698, indicative of its mode of action through the Ras pathway. In summary, we showed that EAPB02303 potently reduced the activity of IIS and Ras-MAPK signaling in . Our results revealed the mechanism of action of EAPB02303 against human cancers associated with hyperactivated IIS pathway and oncogenic Ras mutations.
依美喹啉是免疫调节药物咪喹莫特的类似物。EAPB02303 是第二代依美喹啉的先导化合物，具有显著的抗肿瘤作用，IC50 在纳摩尔范围内。我们使用两种关键信号通路（PI3K-Akt 和 Ras-MAPK）中在人类癌症中发生突变的转基因和突变株来研究 EAPB02303 的作用模式。通过评估野生型蠕虫的寿命，研究了这种依美喹啉通过 PI3K-Akt 激酶级联抑制胰岛素/IGF1 信号通路（IIS）的能力。EAPB02303 的毫摩尔剂量显著延长了 N2 菌株的寿命，并导致转录因子 DAF-16 的核转位和随后的激活，DAF-16 是秀丽隐杆线虫中唯一的叉头框转录因子 O 类（Fox O）同源物。此外，EAPB02303 显著降低了 /Ras 突变株 MT2124 和 MT4698 中的多育表型，表明其通过 Ras 途径发挥作用。总之，我们表明 EAPB02303 能有效降低 IIS 和 Ras-MAPK 信号在秀丽隐杆线虫中的活性。我们的研究结果揭示了 EAPB02303 针对与过度激活的 IIS 途径和致癌性 Ras 突变相关的人类癌症的作用机制。
