PI-273 is a substrate-competitive and specific phosphatidylinositol 4-kinase IIα (PI4KIIα) inhibitor (IC50=0.47μM). PI-273 downregulates PI4P content and inhibits AKT signaling to block cell cycle at G2/M phase and induce apoptosis. PI-273 targets the palmitoylation of PI4KIIα to inhibit phosphatidylinositol signaling pathway. PI-273 can be used for tumor research such as breast cancer[1-4].
In vitro, KBM7 cells were co-treated with 1μM PI-273 and orpinolide for 72 hours. PI-273 did not affect orpinolide-induced cytotoxicity[5]. HEK293 cells stably expressing sGFP(PI4P) were treated with 0.1nM-10μM PI-273 for 3 days. PI-273 inhibited cell proliferation and promoted Golgi PI4P pool accumulation[6]. Drug-resistant 1q21.3-amplified lung adenocarcinoma cells were treated with 5μM PI-273 for 48 hours. PI-273 decreased Golgi-resident PI4P levels and PI4KIIIβ-dependent secretory proteins and inhibited cell proliferation and viability[7].
In vivo, nude mice bearing human lung cancer cells received intraperitoneal injection of 25mg/kg/day PI-273 for 14 days. PI-273 reduced subcutaneous tumor volume and weight, shrank orthotopic lung tumors, decreased metastasis number and prolonged survival time of tumor-bearing mice[8]. BALB/c nude mice inoculated with MCF-7 cells received intraperitoneal injection of 25mg/kg/day PI-273 for 16 days. PI-273 inhibited tumor volume and weight and increased tumor cell apoptosis[9]. NSG mice xenografted with human high-grade serous ovarian cancer cells and TAM mixture received intraperitoneal injection of 25mg/kg PI-273 combined with 5mg/kg cisplatin twice weekly for 60 days. PI-273 reduced subcutaneous xenograft volume of high-grade serous ovarian cancer and TAM mixture[10].
References:[1] Llorente A, Arora GK, Murad R, et al. Phosphoinositide kinases in cancer: from molecular mechanisms to therapeutic opportunities. Nat Rev Cancer. 2025 Jun;25(6):463-487.
[2] Liu DA, Tao K, Wu B, et al. A phosphoinositide switch mediates exocyst recruitment to multivesicular endosomes for exosome secretion. Nat Commun. 2023 Oct 28;14(1):6883.
[3] Manuel SKA, Bilenka E, Gupta M, et al. Dynamic assessment of PI4P metabolism using split GFP based sensors. Sci Rep. 2025 Aug 21;15(1):30805.
[4] Blumrich EM, Nicholson-Fish JC, Pronot M,et al. Phosphatidylinositol 4-kinase IIα is a glycogen synthase kinase 3-regulated interaction hub for activity-dependent bulk endocytosis. Cell Rep. 2023 Jun 27;42(6):112633.
[5] Cigler M, Imrichova H, Frommelt F, et al. Orpinolide disrupts a leukemic dependency on cholesterol transport by inhibiting OSBP. Nat Chem Biol. 2025 Feb;21(2):193-202.
[6] Li J, Huang J, Zeng Y, et al. PI-273, a Substrate-Competitive, specific Small-Molecule inhibitor of PI4KIIalpha, inhibits the growth of breast cancer cells. Cancer Res. 2017 Oct 1;77(21):6253-6266.
[7] Shi L, Tan X, Liu X, et al. Addiction to Golgi-resident PI4P synthesis in chromosome 1q21.3-amplified lung adenocarcinoma cells. Proc Natl Acad Sci U S A. 2021 Jun 21;118(25):e2023537118.
[8] Tan X, Xiao GY, Wang S, et al. EMT-activated secretory and endocytic vesicular trafficking programs underlie a vulnerability to PI4K2A antagonism in lung cancer. J Clin Invest. 2023 Apr 3;133(7):e165863.
[9] Li J, Gao Z, Zhao D, et al. PI-273, a substrate-competitive, specific small molecule inhibitor of PI4KIIa, inhibits the growth of breast cancer cells. Cancer Res. 2017 Oct 1;77(21):6253-6266.
[10] Li J, Lu J, Zheng C, et al. Serotonin-licensed macrophages potentiate chemoresistance via inositol metabolic crosstalk in ovarian cancer. Cell Metab. 2026 Feb 3;38(2):331-349.