GDC-0941

GDC-0941 is an oral, potent, selective pan-inhibitor of class I PI3K, with IC₅₀ values of 3nM, 33nM, 3nM, and 75nM for p110α, p110β, p110δ, and p110γ, respectively^[1]. GDC-0941 inhibits the AKT signaling pathway by suppressing PI3K expression, mainly including the inhibition of AKT phosphorylation as well as phosphorylation levels of AKT downstream proteins^[2]. GDC-0941 has been widely used in both cell and animal models to inhibit the progression of cancer, and has been employed in the development of combined therapies targeting tumors^[3].

In vitro, GDC-0941 treatment for 96 hours significantly inhibited the viability of U87MG, PC3 and MDA-MB-361 cells, with IC₅₀ values of 0.95μM, 0.28μM and 0.72μM, respectively^[4]. Treatment with 10μM GDC-0941 for 48 hours significantly inhibited the proliferation of Daoy cells and induced cell apoptosis, causing the cells to undergo cell cycle arrest^[5]. GDC-0941 (1μM) treatment for 18 hours inhibited hypoxia-induced HIF-1α and HIF-2α expression and HIF activity in thyroid cancer cells^[6].

In vivo, GDC-0941 treatment via oral administration at a dose of 50mg/kg/day for 15 weeks resulted in a significant reduction in the levels of p-Akt-S473 and Ki-67 in the mammary tissues of MMTV-neu mice, delaying tumor occurrence and prolonging the tumor-free survival period^[7]. Oral administration of 100mg/kg/day dose of GDC-0941 for 2 weeks can inhibit tumor growth in RIP1-Tag2 mice without affecting tumor blood vessels^[8].

References:
[1] Sarker D, Ang J E, Baird R, et al. First-in-human phase I study of pictilisib (GDC-0941), a potent pan–class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors[J]. Clinical cancer research, 2015, 21(1): 77-86.
[2] Chen H, Cheng M, Gao P, et al. GDC-0941 activates integrin linked kinase (ILK) expression to cause resistance to GDC-0941 in breast cancer by the tumor necrosis factor (TNF)-α signaling pathway[J]. Bioengineered, 2022, 13(4): 10944-10955.
[3] Usman M W, Gao J, Zheng T, et al. Macrophages confer resistance to PI3K inhibitor GDC-0941 in breast cancer through the activation of NF-κB signaling[J]. Cell death & disease, 2018, 9(8): 809.
[4] Folkes A J, Ahmadi K, Alderton W K, et al. The identification of 2-(1 H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno [3, 2-d] pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer[J]. Journal of medicinal chemistry, 2008, 51(18): 5522-5532.
[5] Ehrhardt M, Craveiro R B, Holst M I, et al. The PI3K inhibitor GDC-0941 displays promising in vitro and in vivo efficacy for targeted medulloblastoma therapy[J]. Oncotarget, 2014, 6(2): 802.
[6] Burrows N, Babur M, Resch J, et al. GDC-0941 inhibits metastatic characteristics of thyroid carcinomas by targeting both the phosphoinositide-3 kinase (PI3K) and hypoxia-inducible factor-1α (HIF-1α) pathways[J]. The journal of clinical endocrinology & metabolism, 2011, 96(12): E1934-E1943.
[7] Wang J, Zhang Y, Xiao Y, et al. Boosting immune surveillance by low-dose PI3K inhibitor facilitates early intervention of breast cancer[J]. American journal of cancer research, 2021, 11(5): 2005.
[8] Soler A, Figueiredo A M, Castel P, et al. Therapeutic benefit of selective inhibition of p110α PI3-kinase in pancreatic neuroendocrine tumors[J]. Clinical Cancer Research, 2016, 22(23): 5805-5817.

GDC-0941是一种口服有效的I类PI3K泛抑制剂，对p110α、p110β、p110δ和p110γ的IC₅₀值分别为3nM、33nM、3nM和75nM^[1]。GDC-0941通过抑制PI3K表达进而阻断AKT信号通路，主要包括抑制AKT及下游蛋白的磷酸化水平^[2]。GDC-0941已广泛应用于细胞和动物模型中抑制肿瘤进展，并用于开发靶向肿瘤的联合疗法^[3]。

在体外，GDC-0941处理96小时能显著抑制U87MG、PC3和MDA-MB-361细胞活力，IC₅₀值分别为0.95μM、0.28μM和0.72μM^[4]。使用10μM的GDC-0941处理Daoy细胞48小时，可显著抑制细胞增殖并诱导细胞凋亡，导致细胞周期阻滞^[5]。用1μM的GDC-0941处理甲状腺癌细胞18小时，能抑制缺氧诱导的HIF-1α和HIF-2α表达及HIF活性^[6]。

在体内，每日口服50mg/kg/day剂量的GDC-0941连续15周，可显著降低MMTV-neu小鼠乳腺组织中p-Akt-S473和Ki-67水平，延缓肿瘤发生并延长无瘤生存期^[7]。每日口服100mg/kg/day剂量的GDC-0941连续2周，能抑制RIP1-Tag2小鼠的肿瘤生长，且不影响肿瘤血管^[8]。