PF-05212384 (PKI-587)

PF-05212384 (PKI-587) is a potent dual PI3K/mTOR inhibitor, exhibiting inhibitory effects against PI3Kα (IC₅₀=0.4nM), PI3Kβ (IC₅₀=6nM), PI3Kγ (IC₅₀=8nM), PI3Kδ (IC₅₀=6nM), and mTOR (IC₅₀=1.4nM)^[1]. PF-05212384 is capable of inhibiting common PI3Kα mutant forms, including H1047R and E545K^[2]. PF-05212384 blocks the PI3K/mTOR signaling pathway by inhibiting the phosphorylation of Akt at threonine 308 (T308) and serine 473 (S473), thereby suppressing the activity of downstream effector proteins such as GSK3 kinase, eNOS, and PRAS40^[3]. PF-05212384 demonstrates significant antitumor activity and is primarily used in cancer-related research^[4].

In vitro, treatment of prostate cancer cells (22RV1, LNCaP) with PF-05212384 (100–1000nM) for 48–72 hours significantly inhibits cell proliferation, induces apoptosis, and effectively blocks the PI3K/AKT/mTOR signaling pathway and its downstream functions^[5]. Treatment of breast cancer cells (MCF7, HCC1428) with PF-05212384 (1.4–9000nM) for 72 hours significantly suppresses cell proliferation, migration, and invasion^[6].

In vivo, administration of PF-05212384 (10mg/kg) in combination with Fulvestrant (10mg/kg; intravenous injection) and/or Palbociclib (30mg/kg; oral) to MCF7 xenograft model mice for 21 days significantly inhibits tumor growth and induces tumor regression^[7]. Intravenous injection of PF-05212384 (25mg/kg; 2–3 times per week) for 4 weeks in six human ovarian cancer xenograft models (OV1002, HOX424, HOX516, HOX552, HOX299, HOX493) significantly suppresses tumor growth and induces apoptosis^[8].

References:
[1] Venkatesan AM, Dehnhardt CM, Delos Santos E, et al. Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5'-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor. J Med Chem. 2010 Mar 25;53(6):2636-45.
[2] Mallon R, Feldberg LR, Lucas J, et al. Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitor. Clin Cancer Res. 2011 May 15;17(10):3193-203.
[3] Dehnhardt CM, Venkatesan AM, Chen Z, et al. Identification of 2-oxatriazines as highly potent pan-PI3K/mTOR dual inhibitors. Bioorg Med Chem Lett. 2011 Aug 15;21(16):4773-8.
[4] Huang Y, Xue X, Li X, et al. Novel nanococktail of a dual PI3K/mTOR inhibitor and cabazitaxel for castration-resistant prostate cancer. Adv Ther (Weinh). 2020 Oct;3(10):2000075.
[5] Sen A, Khan S, Rossetti S, et al. Assessments of prostate cancer cell functions highlight differences between a pan-PI3K/mTOR inhibitor, gedatolisib, and single-node inhibitors of the PI3K/AKT/mTOR pathway. Mol Oncol. 2025 Jan;19(1):225-247.
[6] Rossetti S, Broege A, Sen A, et al. Gedatolisib shows superior potency and efficacy versus single-node PI3K/AKT/mTOR inhibitors in breast cancer models. NPJ Breast Cancer. 2024 Jun 5;10(1):40.
[7] Broege A, Rossetti S, Sen A, et al. Functional Analysis of the PI3K/AKT/mTOR Pathway Inhibitor, Gedatolisib, Plus Fulvestrant with and Without Palbociclib in Breast Cancer Models. Int J Mol Sci. 2025 Jun 18;26(12):5844.
[8] Langdon SP, Kay C, Um IH, et al. Evaluation of the dual mTOR/PI3K inhibitors Gedatolisib (PF-05212384) and PF-04691502 against ovarian cancer xenograft models. Sci Rep. 2019 Dec 10;9(1):18742.

PF-05212384 (PKI-587) 是一种高效的PI3K/mTOR双重抑制剂，对PI3Kα（IC₅₀=0.4nM）、PI3Kβ（IC₅₀=6nM）、PI3Kγ（IC₅₀=8nM）、PI3Kδ（IC₅₀=6nM）和mTOR（IC₅₀=1.4nM）都具有抑制效果^[1]。PF-05212384能够抑制PI3Kα的常见突变形式H1047R和E545K^[2]。PF-05212384通过抑制Akt在苏氨酸308（T308）和丝氨酸473（S473）位点的磷酸化，进而抑制其下游效应蛋白如GSK3激酶、eNOS和PRAS40的活性，从而阻断PI3K/mTOR信号通路^[3]。PF-05212384表现出有效的抗肿瘤活性，主要用于癌症相关的研究^[4]。

在体外，PF-05212384 (100–1000nM) 处理前列腺癌细胞（22RV1、LNCaP）48–72小时，可显著抑制细胞增殖并诱导细胞凋亡，同时有效阻断PI3K/AKT/mTOR信号通路及其下游功能^[5]。PF-05212384（1.4-9000nM）处理乳腺癌细胞（MCF7、HCC1428）72小时，可显著抑制细胞增殖、迁移与侵袭^[6]。

在体内，PF-05212384（10mg/kg）联合Fulvestrant（10mg/kg；静脉注射）和/或Palbociclib（30mg/kg；口服），用于处理MCF7异种移植瘤模型小鼠21天，显著抑制肿瘤生长并诱导肿瘤消退^[7]。PF-05212384（25mg/kg）静脉注射（每周2-3次），用于处理六种人源卵巢癌异种移植瘤模型（OV1002、HOX424、HOX516、HOX552、HOX299、HOX493）小鼠4周，显著抑制肿瘤生长并诱导凋亡^[8]。