AGX51 is the first pan-Id (DNA binding/differentiation protein inhibitor) antagonist and degrader. It inhibits the interaction between Id1 and E47 protein, induces ubiquitin-mediated degradation of Ids protein, thereby inhibiting cell growth and reducing cell viability[1]. AGX51 can inhibit the formation of pathological ocular neovascularization and can also be used in cancer research[2, 3].
In vitro, AGX51 (0-60μM) treatment of breast cancer cell lines (4T1 and nine other cell lines) for 24-72h significantly inhibited cell growth and viability[4]. AGX51 (0-40μM) treatment of INA-6 BRE-luc cells reduced luciferase activity after BMP9 treatment, and this reduction was not dependent on cell death[5]. AGX51 (40μM) treatment of MDA-MB-231 cells for 72h significantly inhibited cell proliferation and significantly reduced Ki67 expression[6].
In vivo, AGX51 (15mg/kg) was intraperitoneally injected into mice bearing MDA-MB-231 cell xenografts for 12 days, significantly inhibiting tumor growth[6]. AGX51 (30mg/kg) was intraperitoneally injected into mice bearing low oscillatory shear stress (OSS)-mediated atherosclerosis for 4 weeks, significantly inhibiting the expression of ID1 protein, reducing foam cells, restoring intimal thickness, and inhibiting lipid and collagen fiber deposition caused by OSS[7].
References:
[1] Lighter D J. Characterization of the Inhibitor of Differentiation (ID) Family in Ovarian Cancer[D]. San Diego State University, 2023.
[2] Wojnarowicz P M, e Silva R L, Ohnaka M, et al. A small-molecule pan-id antagonist inhibits pathologic ocular neovascularization[J]. Cell reports, 2019, 29(1): 62-75. e7.
[3] Zhong G, Wang Y, Wang Q, et al. Discovery of novel ID2 antagonists from pharmacophore-based virtual screening as potential therapeutics for glioma[J]. Bioorganic & Medicinal Chemistry, 2021, 49: 116427.
[4] Wojnarowicz P M, Escolano M G, Huang Y H, et al. Anti-tumor effects of an ID antagonist with no observed acquired resistance[J]. NPJ Breast Cancer, 2021, 7(1): 58.
[5] Møen J. FKBP12 and regulation of ALK2-and ALK3-ligand activity in multiple myeloma cells[D]. NTNU, 2024.
[6] Toro C D, Real S M, Laurito S R, et al. Exploring ID4 as a Driver of Aggression and a Therapeutic Target in Triple-Negative Breast Cancer[J]. bioRxiv, 2025: 2025.02. 07.637072.
[7] Jun Q, Yang X, Wang B, et al. ID1 protein inhibitor depresses low-oscillating shear stress-mediated EndMT and atherosclerosis by Snail and Wnt/β-catenin signalling pathways[J]. 2024.
AGX51是首个pan-Id（DNA结合/分化蛋白抑制剂）拮抗剂和降解剂，通过抑制Id1与E47蛋白的相互作用，诱导泛素介导的Ids蛋白降解，从而抑制细胞生长并降低细胞活力[1]。AGX51能够抑制病理性眼部新生血管的形成，还能够用于癌症研究[2, 3]。
在体外，AGX51（0-60μM）处理乳腺癌细胞系（4T1和其他九种细胞）24-72h，显著抑制了细胞的生长和活力[4]。AGX51（0-40μM）处理INA-6 BRE-luc细胞，降低了BMP9处理后的荧光素酶活性，并且这种降低并不依赖于细胞死亡[5]。AGX51（40μM）处理MDA-MB-231细胞72h，显著抑制了细胞增殖，显著减少了Ki67的表达[6]。
在体内，AGX51（15mg/kg）通过腹腔注射治疗MDA-MB-231细胞异种移植小鼠12天，显著抑制了肿瘤生长[6]。AGX51（30mg/kg）通过腹腔注射治疗低振荡剪切应力（OSS）介导的动脉粥样硬化小鼠4周，显著抑制了ID1蛋白的表达，减少了泡沫细胞，恢复了内膜厚度，抑制了OSS引起的脂质沉积及胶原纤维沉积[7]。