SNX-2112

SNX-2112 is a potent inhibitor of synthetic heat shock protein (Hsp 90) with an IC₅₀ value of 30nM^[1]. SNX-2112 inhibits tube formation by human umbilical vein endothelial cells via abrogation of the eNOS/Akt pathway and markedly inhibits osteoclast formation via down-regulation of ERK/c-fos and PU.1^[2]. SNX-2112 has been widely used to inhibit tumor progression as well as to induce degradation of HSP-90 substrate proteins in cellular and animal models^[3].

In vitro, SNX-2112 treatment for 72 hours significantly inhibited the viability of HepG2, Huh7, and SK-Hep1 cells, with IC₅₀ values of 0.36μM, 0.12μM and 0.24μM, respectively^[4]. Treatment with 125nM SNX-2112 for 48 hours inhibited Akt/mTOR signaling pathway, upregulated LC3-II and Beclin1 expression, and induced autophagy in HeLa cells^[5]. Treatment with SNX-2112 at 0.2µM for 48h significantly induced apoptosis in A-375 cells, accompanied by chromatin condensation, marginalization, and DNA fragmentation^[6].

In vivo, SNX-2112 treatment via oral administration at a daily dose of 80mg/kg for 15 days significantly inhibited tumor growth in a B16 cell xenograft tumor mouse model and resulted in a reduction in intratumoral vessel density^[7]. Intravenous injection of 6mg/kg SNX-2112 (five times a week) for two consecutive weeks significantly inhibited the expression levels of CD13⁺ and CD33⁺ in NOD/SCID mice inoculated with K562 cells and prolonged the survival time of the mice^[8].

References:
[1] Chandarlapaty S, Sawai A, Ye Q, et al. SNX2112, a synthetic heat shock protein 90 inhibitor, has potent antitumor activity against HER kinase–dependent cancers[J]. Clinical Cancer Research, 2008, 14(1): 240-248.
[2] Okawa Y, Hideshima T, Steed P, et al. SNX-2112, a selective Hsp90 inhibitor, potently inhibits tumor cell growth, angiogenesis, and osteoclastogenesis in multiple myeloma and other hematologic tumors by abrogating signaling via Akt and ERK[J]. Blood, The Journal of the American Society of Hematology, 2009, 113(4): 846-855.
[3] Bachleitner-Hofmann T, Sun M Y, Chen C T, et al. Antitumor activity of SNX-2112, a synthetic heat shock protein-90 inhibitor, in MET-amplified tumor cells with or without resistance to selective MET Inhibition[J]. Clinical Cancer Research, 2011, 17(1): 122-133.
[4] Wang X, Wang S, Liu Y, et al. The Hsp90 inhibitor SNX-2112 induces apoptosis of human hepatocellular carcinoma cells: the role of ER stress[J]. Biochemical and biophysical research communications, 2014, 446(1): 160-166.
[5] Hu L, Wang Y, Chen Z, et al. Hsp90 inhibitor SNX‐2112 enhances TRAIL‐Induced apoptosis of human cervical cancer cells via the ROS‐mediated JNK‐p53‐autophagy‐DR5 pathway[J]. Oxidative medicine and cellular longevity, 2019, 2019(1): 9675450.
[6] Liu K S, Liu H, Qi J H, et al. SNX-2112, an Hsp90 inhibitor, induces apoptosis and autophagy via degradation of Hsp90 client proteins in human melanoma A-375 cells[J]. Cancer letters, 2012, 318(2): 180-188.
[7] Liu K S, Ding W C, Wang S X, et al. The heat shock protein 90 inhibitor SNX-2112 inhibits B16 melanoma cell growth in vitro and in vivo[J]. Oncology reports, 2012, 27(6): 1904-1910.
[8] Jin L, Xiao C L, Lu C H, et al. Transcriptomic and proteomic approach to studying SNX-2112-induced K562 cells apoptosis and anti-leukemia activity in K562-NOD/SCID mice[J]. FEBS letters, 2009, 583(12): 1859-1866.

SNX-2112是一种强效的合成型热休克蛋白（Hsp 90）抑制剂，IC₅₀值为30nM^[1]。SNX-2112通过阻断eNOS/Akt通路抑制人脐静脉内皮细胞的管腔形成，并通过下调ERK/c-fos和PU.1显著抑制破骨细胞的形成^[2]。SNX-2112已被广泛用于在细胞和动物模型中抑制肿瘤进展，并诱导HSP-90底物蛋白降解^[3]。

在体外，SNX-2112处理72小时显著抑制了HepG2、Huh7和SK-Hep1细胞的活力，IC₅₀值分别为0.36µM、0.12µM和0.24µM^[4]。使用125nM的SNX-2112处理48小时，抑制了HeLa细胞中的Akt/mTOR信号通路，上调了LC3-II和Beclin1的表达，并诱导了细胞自噬^[5]。使用0.2µM的SNX-2112处理48小时，显著诱导了A-375细胞凋亡，伴随染色质浓缩、边缘化及DNA片段化^[6]。

在体内，每日口服给予80mg/kg剂量的SNX-2112，持续15天，显著抑制了B16细胞异种移植肿瘤小鼠模型中的肿瘤生长，并降低了瘤内血管密度^[7]。连续两周每周五次静脉注射6mg/kg剂量的SNX-2112，显著抑制了接种K562细胞的NOD/SCID小鼠中CD13⁺和CD33⁺的表达水平，并延长了小鼠的存活时间^[8]。