KG-501 (Naphthol AS-E phosphate) is a small molecule compound that can inhibit the interaction between cAMP response element-binding protein (CREB) and CREB-binding protein (CBP), with an IC₅₀ value of 6.89μM[1]. KG-501 directly targets the KIX domain of CBP to disrupt the binding of phosphorylated CREB (Ser-133) to KIX (Kᵢ ≈ 90μM), thereby inhibiting the transcriptional activity of cAMP-related genes[2]. KG-501 can inhibit the expression of endogenous CREB target genes (NR4A2, c-fos) induced by forskolin in cellular models and promote the recovery of neural function[3]. KG-501 can also inhibit IL-1β-mediated CXC chemokine expression and angiogenic activity in non-small cell lung cancer[4].
In vitro, pre-treatment of C2C12 myoblasts with KG-501 (250μM) for 30 minutes to 2 hours, followed by stimulation with IFN-γ (60ng/ml) for 72 hours, significantly inhibits the mRNA accumulation of CREB pathway molecules (CREB1, Bcl-xl, MEF-2) and the protein expression level of p-CREB1, while reducing the gene expression of inflammation-related cytokines (IL-1β, IL-6, TNF-α) and chemokines (MIP-1α, MCP-1)[5]. Pre-treatment of the human colorectal cancer cell line SW480 with KG-501 (5–25μM) for 24 hours significantly inhibits cell migration and invasion capabilities, while reducing the transcriptional and enzymatic activities of matrix metalloproteinases (MMP-2/MMP-9)[6].
In vivo, intracerebroventricular infusion of KG-501 (10–50μM; 3-5μL) in C57BL/6 mice for 3 days, followed by a single intraperitoneal injection of azoxymethane (AOM, 100mg/kg) to induce acute liver failure and hepatic encephalopathy, significantly accelerates AOM-induced neurofunctional decline (manifested as decreased neuroscore and shortened coma time), while inhibiting CREB protein expression, CCL2 inflammatory factor release, and ERK phosphorylation levels in the cortex, and reducing cAMP concentrations[7].
References:
[1] Lee JW, Park HS, Park SA, et al. A Novel Small-Molecule Inhibitor Targeting CREB-CBP Complex Possesses Anti-Cancer Effects along with Cell Cycle Regulation, Autophagy Suppression and Endoplasmic Reticulum Stress. PLoS One. 2015 Apr 21;10(4):e0122628.
[2] Best JL, Amezcua CA, Mayr B, et al. Identification of small-molecule antagonists that inhibit an activator: coactivator interaction. Proc Natl Acad Sci U S A. 2004 Dec 21;101(51):17622-7.
[3] Chiu SP, Wu MJ, Chen PY, et al. Neurotrophic action of 5-hydroxylated polymethoxyflavones: 5-demethylnobiletin and gardenin A stimulate neuritogenesis in PC12 cells. J Agric Food Chem. 2013 Oct 2;61(39):9453-63.
[4] Sun H, Chung WC, Ryu SH, et al. Cyclic AMP-responsive element binding protein- and nuclear factor-kappaB-regulated CXC chemokine gene expression in lung carcinogenesis. Cancer Prev Res (Phila). 2008 Oct;1(5):316-28.
[5] Gu R, Ding M, Shi D, et al. Calcium/Calmodulin-Dependent Protein Kinase IV Mediates IFN-γ-Induced Immune Behaviors in Skeletal Muscle Cells. Cell Physiol Biochem. 2018;46(1):351-364.
[6] Steven A, Heiduk M, Recktenwald CV, et al. Colorectal Carcinogenesis: Connecting K-RAS-Induced Transformation and CREB Activity In Vitro and In Vivo. Mol Cancer Res. 2015 Aug;13(8):1248-62.
[7] Woo JT, Yamaguchi K, Hayama T, et al. Suppressive effect of N-(benzyloxycarbonyl)-L-phenylalanyl-L-tyrosinal on bone resorption in vitro and in vivo. Eur J Pharmacol. 1996 Apr 4;300(1-2):131-5.
KG-501 (Naphthol AS-E phosphate) 是一种能够抑制cAMP反应元件结合蛋白（CREB）与CREB结合蛋白（CBP）相互作用的小分子化合物，其IC₅₀值为6.89μM[1]。KG-501通过直接靶向CBP的KIX结构域，破坏磷酸化CREB（Ser-133）与KIX的结合（Kᵢ ≈ 90μM），从而抑制cAMP相关基因的转录活性[2]。KG-501在细胞模型中能够抑制由佛司可林诱导的内源性CREB靶基因（NR4A2、c-fos）的表达，促进神经功能恢复[3]。KG-501还可抑制非小细胞肺癌中IL-1β介导的CXC趋化因子表达及血管生成活性[4]。
在体外，KG-501（250μM）预处理C2C12成肌细胞30分钟至2小时，随后以IFN-γ（60ng/ml）刺激72小时，显著抑制CREB通路分子（CREB1、Bcl-xl、MEF-2）的mRNA积累及p-CREB1蛋白表达水平，同时降低炎症相关细胞因子（IL-1β、IL-6、TNF-α）和趋化因子（MIP-1α、MCP-1）的基因表达[5]。KG-501（5–25μM）预处理人结肠癌细胞系SW480细胞24小时，显著抑制细胞迁移和侵袭能力，同时降低基质金属蛋白酶（MMP-2/MMP-9）的转录活性及酶活性[6]。
在体内，KG-501（10–50μM；3-5μL）通过侧脑室灌注预处理C57BL/6小鼠3天，随后以偶氮甲烷（AOM，100mg/kg）单次腹腔注射诱导急性肝衰竭及肝性脑病。KG-501显著加速AOM诱导的神经功能衰退（表现为神经评分下降及昏迷时间缩短），同时抑制皮层中CREB蛋白表达、CCL2炎性因子释放及ERK磷酸化水平，并降低cAMP浓度[7]。