Alamodi Alghamdi Maha, Deshpande Hemali
Department of Surgery, College of Medicine, King Khalid University, Abha, Saudi Arabia.
Department of Anatomy, College of Medicine, King Khalid University, Abha, Saudi Arabia.
Biochem Biophys Res Commun. 2025 Mar 1;750:151382. doi: 10.1016/j.bbrc.2025.151382. Epub 2025 Jan 25.
Melanoma, a highly aggressive skin cancer is frequently driven by the BRAF mutation. Vemurafenib initially offers clinical benefits but often encounters resistance due to secondary mutations and compensatory signaling pathways. Targeting p300, a histone acetyltransferase involved in transcriptional regulation and resistance mechanisms, presents a potential strategy to overcome this therapeutic challenge.
A virtual screening was conducted to identify small molecules targeting p300. Molecular dynamics simulations (MDS), Root Mean Square Deviation (RMSD), and Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) were employed for computational predictions. Normal (A2058, A375, and SK-MEL-28) and vemurafenib-resistant A2058, A375 , and SK-MEL-28 melanoma cells were used for cell-based assays.
EPS496 was identified as a p300 inhibitor, demonstrating high binding stability with a low RMSD value during the MDS. MMPBSA analysis revealed highly favorable binding energy, indicating strong and stable interaction with p300. EPS496 effectively inhibited the proliferation of normal melanoma cells with GI values of 367.8 nM, 986.4 nM, and 642.1 nM in A375, SK-MEL-28, and A2058 respectively. The compound retained the anti-proliferative efficacy in the resistant A375, SK-MEL-28, and A2058 with respective GI values of 345.6 nM, 1018 nM, and 708.5 nM. Whereas vemurafenib was less active several folds in the resistant cells. EPS496 promoted early, and phase apoptosis and reduced p300-positive populations in the vemurafenib-resistant melanoma cells.
EPS496, through its inhibition of p300, provides a novel approach to counteract vemurafenib resistance in melanoma. Results highlight its potential to be developed as an effective therapeutic agent for combating melanoma.
黑色素瘤是一种侵袭性很强的皮肤癌，通常由BRAF突变驱动。维莫非尼最初可带来临床益处，但由于继发突变和代偿性信号通路，常常会产生耐药性。靶向p300（一种参与转录调控和耐药机制的组蛋白乙酰转移酶）是克服这一治疗挑战的潜在策略。
进行虚拟筛选以鉴定靶向p300的小分子。采用分子动力学模拟（MDS）、均方根偏差（RMSD）和分子力学泊松-玻尔兹曼表面积（MMPBSA）进行计算预测。使用正常（A2058、A375和SK-MEL-28）以及对维莫非尼耐药的A2058、A375和SK-MEL-28黑色素瘤细胞进行基于细胞的检测。
EPS496被鉴定为一种p300抑制剂，在MDS期间显示出高结合稳定性和低RMSD值。MMPBSA分析显示出高度有利的结合能，表明与p300有强而稳定的相互作用。EPS496有效抑制正常黑色素瘤细胞的增殖，在A375、SK-MEL-28和A2058中的GI值分别为367.8 nM、986.4 nM和642.1 nM。该化合物在耐药的A375、SK-MEL-28和A2058中保留了抗增殖功效，其GI值分别为345.6 nM、1018 nM和708.5 nM。而维莫非尼在耐药细胞中的活性则低几倍。EPS496促进了对维莫非尼耐药的黑色素瘤细胞的早期凋亡和阶段凋亡，并减少了p300阳性群体。
EPS496通过抑制p300，为对抗黑色素瘤中的维莫非尼耐药性提供了一种新方法。结果突出了其作为一种有效治疗黑色素瘤的治疗药物的开发潜力。
