ISA-2011B, a diketopiperazine fused C-1 indol-3-yl substituted tetra-hydro-isoquinoline, specifically inhibiting the PIP5Kα and the related AKT pathways[1]. ISA-2011B acts as a novel type of anticancer compound that targets PCa cells by targeting AKT/AR-related pathways without toxicity[2].
In vitro, ISA-2011B treatment in primary T cells and Jurkat cells at 25µM for 6h strongly impaired CD3/CD28-mediated induction of PIP5Kα kinase activity and reduced IL-2 mRNA levels, accompanied by cell death[3]. Treatment of C4-2 cells with 50µM ISA-2011B for 48h resulted in a significant down-regulation of cyclin A1, inhibition of cell proliferation and migration, and a decrease in the expression of phosphorylated Ser-473 AKT[4]. Treatment of PC-3 cells with 25µM ISA-2011B for 48 hours resulted in a significant increase in both early and late apoptosis/necrosis[5].
In vivo, ISA-2011B treatment via intraperitoneal injection (40mg/kg; once every other day; i.p.) for 24 days significantly inhibited tumor growth and invasion in the xenograft tumor mouse models[6]. Intraperitoneal injection of ISA-2011B at a dose of 40mg/kg (once every other day) for 15 days suppressed the aggressive growth of AR-V7-overexpressing tumors in xenograft mice, disrupting the PIP5K1α-dependent protein stability of AR-V7[7].
References:
[1] Jin Y, Xue J. Lipid kinases PIP5Ks and PIP4Ks: potential drug targets for breast cancer[J]. Frontiers in Oncology, 2023, 13: 1323897.
[2] Yin M, Wang Y. The role of PIP5K1A in cancer development and progression[J]. Medical Oncology, 2022, 39(10): 151.
[3] Kunkl M, Porciello N, Mastrogiovanni M, et al. ISA-2011B, a phosphatidylinositol 4-phosphate 5-kinase α inhibitor, impairs CD28-dependent costimulatory and pro-inflammatory signals in human T lymphocytes[J]. Frontiers in Immunology, 2017, 8: 502.
[4] Wang T, Sarwar M, Whitchurch J B, et al. PIP5K1α is required for promoting tumor progression in castration-resistant prostate cancer[J]. Frontiers in cell and developmental biology, 2022, 10: 798590.
[5] Semenas J, Wang T, Sajid Syed Khaja A, et al. Targeted inhibition of ERα signaling and PIP5K1α/Akt pathways in castration‐resistant prostate cancer[J]. Molecular Oncology, 2021, 15(4): 968-986.
[6] Sarwar M, Syed Khaja A S, Aleskandarany M, et al. The role of PIP5K1α/pAKT and targeted inhibition of growth of subtypes of breast cancer using PIP5K1α inhibitor[J]. Oncogene, 2019, 38(3): 375-389.
[7] Sarwar M, Semenas J, Miftakhova R, et al. Targeted suppression of AR-V7 using PIP5K1α inhibitor overcomes enzalutamide resistance in prostate cancer cells[J]. Oncotarget, 2016, 7(39): 63065.
ISA-2011B是一种二酮哌嗪并合的C-1吲哚-3-基取代四氢异喹啉类化合物，可特异性抑制PIP5Kα及相关AKT信号通路 [1]。ISA-2011B是一种新型抗癌剂，通过靶向AKT/AR相关通路选择性作用于前列腺癌细胞，且不产生毒性作用[2]。
在体外，25µM 的ISA-2011B处理原代T细胞和Jurkat细胞6小时，可显著抑制CD3/CD28介导的PIP5Kα激酶活性升高，降低IL-2 mRNA水平并引发细胞死亡[3]。50µM的ISA-2011B处理C4-2细胞48小时能显著下调细胞周期蛋白A1表达，抑制细胞增殖与迁移，并降低磷酸化Ser-473 AKT水平[4]。25µM的ISA-2011B处理PC-3细胞48小时可显著增加早期与晚期凋亡/坏死率[5]。
在体内，异种移植瘤小鼠模型经腹腔注射ISA-2011B（40mg/kg；隔日一次；持续24天）后，肿瘤生长和侵袭被显著抑制[6]。AR-V7过表达的异种移植小鼠经腹腔注射ISA-2011B（40mg/kg；隔日一次；持续15天）后，肿瘤侵袭性生长受到抑制，ISA-2011B破坏了PIP5K1α依赖的AR-V7蛋白稳定性[7]。