A-485 is a potent and selective p300/CBP (histone acetyltransferase paralog/CREB binding protein) catalytic inhibitor with IC50 of 60nM for p300 HAT. A-485 inhibits the activity of p300-BHC (bromodomain HAT-C/H3) and CBP-BHC domains with IC50 of 9.8nM and 2.6nM, respectively. A-485 selectively inhibits the proliferation of lineage-specific tumor types, including several hematological malignancies and androgen receptor-positive prostate cancer [1-2].
A-485 reduces the level of acetylated histone H3 lysine 27 (H3K27Ac) in PC3 cells in a concentration-dependent manner with an EC50 of 73nM, but has little effect on H3K9Ac (EC50 > 10mM) [1]. A-485 has an inhibitory effect on H3K27Ac in three melanoma cell lines (WM2664, SKMEL5 and A375 cells) with IC50 of 0.59, 0.93 and 0.96μM, respectively. A-485 significantly induces cell senescence in sensitive melanoma cell lines WM2664 and SKMEL5, but no similar effect was observed in resistant A375 cells [3].
A-485 reduced tumor volume (54%) in the LuCaP-77 CR mouse xenograft model of castration-resistant prostate cancer when administered at a dose of 100mg/kg for 21 days [1]. In the GH3 cell xenograft nude mouse model, A-485 can significantly inhibit tumor volume (50mg/kg group inhibited 32.37%, 100mg/kg group inhibited 54.15%) and tumor weight (50mg/kg group inhibited 43.83% , the 100mg/kg group inhibited 61.41%) [4].
References:
[1] Lasko LM, et al. Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours. Nature. 2017 Oct 5;550(7674):128-132.
[2] Tottone L, Zhdanovskaya N, Carmona Pestaña Á, Zampieri M, Simeoni F, Lazzari S, Ruocco V, Pelullo M, Caiafa P, Felli MP, Checquolo S, Bellavia D, Talora C, Screpanti I, Palermo R. Histone Modifications Drive Aberrant Notch3 Expression/Activity and Growth in T-ALL. Front Oncol. 2019 Apr 3;9:198.
[3] Wang R, He Y, Robinson V, Yang Z, Hessler P, Lasko LM, Lu X, Bhathena A, Lai A, Uziel T, Lam LT. Targeting Lineage-specific MITF Pathway in Human Melanoma Cell Lines by A-485, the Selective Small-molecule Inhibitor of p300/CBP. Mol Cancer Ther. 2018 Dec;17(12):2543-2550.
[4] Ji C, Xu W, Ding H, et al. The p300 inhibitor A-485 exerts antitumor activity in growth hormone pituitary adenoma[J]. The Journal of Clinical Endocrinology & Metabolism, 2022, 107(6): e2291-e2300.
A-485是有效的选择性p300/CBP（组蛋白乙酰转移酶旁系同源物/CREB结合蛋白）的催化抑制剂，对p300 HAT的IC50值为60nM。A-485可抑制p300-BHC（溴域HAT-C/H3）和CBP-BHC结构域的活性，IC50分别为9.8nM和2.6nM。A-485可选择性抑制谱系特异性肿瘤类型的增殖，包括几种血液系统恶性肿瘤和雄激素受体阳性前列腺癌[1-2]。
A-485以浓度依赖性方式降低PC3细胞中的乙酰化组蛋白H3赖氨酸27（H3K27Ac）水平，EC50为73nM，但对H3K9Ac影响较小（EC50 > 10mM）[1]。A-485对三种黑色素瘤细胞系（WM2664、SKMEL5和A375细胞）的H3K27Ac均有抑制作用，IC50 分别为0.59、0.93和0.96μM，并且A-485在敏感的黑色素瘤细胞系WM2664和SKMEL5中明显诱导细胞衰老，但在耐药系A375细胞中未观察到类似效果[3]。
当以100mg/kg的剂量给药21天时，A-485在去势抵抗性前列腺癌的LuCaP-77 CR小鼠异种移植模型中可减少肿瘤体积（54%）[1]。在GH3细胞异种移植裸鼠模型中，A-485可显著抑制肿瘤体积（50mg/kg组抑制32.37%，100mg/kg组抑制54.15%）和肿瘤重量（50mg/kg组抑制43.83%，100mg/kg组抑制61.41%）[4]。