Butyrolactone 3 is a small molecule inhibitor of the histone acetyltransferase GCN5 (IC50 = 100μM) [1]. Butyrolactone 3 inhibits the catalytic activity of GCN5 to reduce histone acetylation levels and block downstream GCN5 signaling pathways, thereby disrupting tumor cell survival mechanisms [2-3]. Butyrolactone 3 is primarily used to treat lymphoma [4].
In C3H10T1/2 cells, Butyrolactone 3 (100μM; 4 weeks) inhibits the expression of Gcn5 after islet-1 transfection [5]. In H3K9ac cells, Butyrolactone 3 (0-200μM; 48h) inhibits GCN5 HAT activity and thus reduces the viability of burkitt lymphoma cells [6].
In ovarian cancer PDX mice model, Butyrolactone 3 (5mg/kg; ip; 30d) can increase the sensitivity of ovarian cancer cases to Cisplatin and even reverse their resistance [7]. In streptozotocin and a high fat diet rat model, Butyrolactone 3 (1mg/kg; nasal administrated; 8 weeks) attenuates increase in GCN5, H3K9 histone hyperacetylation on CDK5 promoter, and CDK5 upregulation [8].
References:
[1]. Mai A, Rotili D, Tarantino D, et al. Small-molecule inhibitors of histone acetyltransferase activity: identification and biological properties[J]. Journal of medicinal chemistry, 2006, 49(23): 6897-6907.
[2]. Haque M E, Jakaria M, Akther M, et al. The GCN5: its biological functions and therapeutic potentials[J]. Clinical Science, 2021, 135(1): 231-257.
[3]. Luan J, Chu Z, Chandra J, et al. Small molecular inhibitors targeting chromatin regulating proteins for cancer[J]. Current Protein and Peptide Science, 2016, 17(5): 455-462.
[4]. Gong Y, Fu W. Reversible role of MIR654/3P and MIR9/3P in pathogenesis of Epstein-Barr virus–negative, but not Epstein-Barr virus–positive, Burkitt lymphoma[J]. Journal of Leukocyte Biology, 2025, 117(3): qiae237.
[5]. Xu H, Zhou Q, Yi Q, et al. Islet-1 synergizes with Gcn5 to promote MSC differentiation into cardiomyocytes[J]. Scientific Reports, 2020, 10(1): 1817.
[6]. Farria A T, Mustachio L M, Akdemir Z H C, et al. GCN5 HAT inhibition reduces human Burkitt lymphoma cell survival through reduction of MYC target gene expression and impeding BCR signaling pathways[J]. Oncotarget, 2019, 10(56): 5847.
[7]. Sun C, Li X, Teng Q, et al. Targeting platinum-resistant ovarian cancer by disrupting histone and RAD51 lactylation[J]. Theranostics, 2025, 15(7): 3055.
[8]. Cai H B, Fan Z Z, Tian T, et al. Diabetes-induced H3K9 hyperacetylation promotes development of Alzheimer’s disease through CDK5[J]. Journal of Alzheimer’s Disease, 2020, 77(1): 75-84.
Butyrolactone 3是组蛋白乙酰转移酶GCN5的小分子抑制剂（IC50 = 100μM） [1]。Butyrolactone 3通过抑制GCN5的催化活性来降低组蛋白乙酰化水平，并阻断下游GCN5信号通路，从而破坏肿瘤细胞的存活机制 [2-3]。Butyrolactone 3主要用于治疗淋巴瘤 [4]。
在C3H10T1/2细胞中，Butyrolactone 3（100µM；4周）可抑制islet-1转染后Gcn5的表达 [5]。在H3K9ac细胞中，Butyrolactone 3（0-200μM；48h）可抑制GCN5 HAT活性，从而降低伯基特淋巴瘤细胞的存活率 [6]。
在卵巢癌PDX小鼠模型中，Butyrolactone 3（5mg/kg；ip；30d）可以增加卵巢癌病例对顺铂的敏感性，甚至逆转其耐药性 [7]。在链脲佐菌素和高脂饮食大鼠模型中，Butyrolactone 3（1mg/kg；鼻腔给药；8周）可以减弱GCN5、H3K9组蛋白在CDK5启动子上的高乙酰化以及CDK5的上调 [8]。