HA15 is a molecule that specifically targets BiP/GRP78/HSPA5, binding to and inhibiting its ATPase activity, which leads to the dissociation of BiP from PERK, IRE1α, and ATF6, thereby triggering endoplasmic reticulum stress[1][2][3]. HA15 has demonstrated anti-tumor effects in a variety of human cancers, including melanoma, breast, pancreas, and adrenocortical carcinoma[2].
HA15 (1-10μM, 24h) decreases melanoma cell viability in a dose-dependent manner compared with control conditions (DMSO), with an IC50 of 1-2.5μM in A375 cells[1]. HA15 (10μM, 48h) induces typical dilated endoplasmic reticulum cisternae in A375 cells[1]. HA15 (1, 5 and 10μM; 48h) induces apoptosis in A375 cells by increasing the levels of the cleaved and activated form of caspase 9 and decreasing the levels of the zymogenic form of caspase 3[1].
HA15 (0.7mg/mouse, 5 days/week, 5 weeks, i.p.) treatment delayed tumor growth in malignant pleural mesothelioma (MPM) mouse model[2]. HA15 (0.5mg/kg twice weekly, 3 weeks, i.p.) in combination with BTZ, was more effective at inhibiting tumor growth than BTZ alone in a multiple myeloma mouse model[4].
References:
[1] Cerezo M, Lehraiki A, Millet A, et al. Compounds Triggering ER Stress Exert Anti-Melanoma Effects and Overcome BRAF Inhibitor Resistance. Cancer Cell. 2016 Jun 13;29(6):805-819.
[2] Xu D, Yang H, Yang Z, et al. Endoplasmic Reticulum Stress Signaling as a Therapeutic Target in Malignant Pleural Mesothelioma. Cancers (Basel). 2019 Oct 8;11(10):1502.
[3] Ruggiero C, Doghman-Bouguerra M, Ronco C, et al. The GRP78/BiP inhibitor HA15 synergizes with mitotane action against adrenocortical carcinoma cells through convergent activation of ER stress pathways. Mol Cell Endocrinol. 2018 Oct 15;474:57-64.
[4] Chen Y, Tao Y, Hu K, et al. GRP78 inhibitor HA15 increases the effect of Bortezomib on eradicating multiple myeloma cells through triggering endoplasmic reticulum stress. Heliyon. 2023 Sep 2;9(9):e19806.
HA15是一种特异性靶向BiP/GRP78/HSPA5的分子，可结合并抑制其ATPase活性，导致BiP与PERK、IRE1α和ATF6分离，从而引发内质网应激[1][2][3]。HA15已证明对多种人类癌症具有抗肿瘤作用，包括黑色素瘤、乳腺癌、胰腺癌和肾上腺皮质癌[2]。
与对照条件（DMSO）相比，HA15（1-10μM，24h）以剂量依赖性方式降低黑色素瘤细胞活力，在A375细胞中的IC50为1-2.5μM[1]。HA15（10μM，48h）诱导A375细胞中典型的扩张内质网池[1]。HA15（1、5和10μM，48小时）通过增加caspase 9的裂解和活化形式水平并降低caspase 3的酶原形式水平来诱导A375细胞凋亡[1]。
HA15（0.7mg/只小鼠，每周5天，5周，腹腔注射）治疗可延缓恶性胸膜间皮瘤（MPM）小鼠模型中的肿瘤生长[2]。HA15（0.5mg/kg，每周两次，3周，腹腔注射）与BTZ联合使用，在多发性骨髓瘤小鼠模型中抑制肿瘤生长的效果比单独使用BTZ更好[4]。