SBI-0640756 (SBI-756) (SBI-756) is a first-in-class inhibitor that targets eIF4G1 and disrupts the eIF4F complex.

SBI-0640756有效地以剂量依赖的方式使eIF4G1与eIF4E解离，伴随着4E-BP1:eIF4E结合的同时增加，反映了eIF4F复合体形成受损。SBI-0640756还抑制了AKT/mTORC1信号传导，并且mTORC1的抑制通过激活4E-BPs破坏eIF4F复合体。尽管torin1在WT中诱导eIF4G1与eIF4E的解离，但在4E-BP DKO MEFs中并没有此效果，SBI-0640756在WT和4E-BP DKO MEFs中均降低了eIF4G1:eIF4E的关联。同样，SBI-0640756而非torin1降低了E1A/RAS转化的4E-BP DKO MEFs的增殖。

在Ink4a 基因失活并诱导NRasQ61E后11周开始仅施用SBI-0640756（大约在肿瘤出现前10-14天），与对照组未经治疗的动物相比，能够延迟肿瘤发生时间（从20-26周开始）并且将肿瘤发生率降低了50%。对于已经形成的肿瘤，仅使用BRAFi治疗或BRAFi加SBI-0640756的组合治疗都能显著抑制肿瘤的生长。

Cells were rinsed with PBS and lysed as previously described. Protein concentration was determined using Coomassie Plus Protein Assay Reagent. Equal amounts of cell lysate proteins (50 μg) were separated on SDS-PAGE and transferred to polyvinylidene difluoride membranes. Membranes were blocked (5% BSA/TBST, 1 h) and incubated with primary antibodies (1 h at room temperate or overnight at 4°C), with shaking. Following three TBST washes, membranes were incubated for 1 h at room temperature secondary antibodies (1:10,000). Detection and quantifications were made using Odyssey Infrared Imaging System, or by exposing them to X-ray film. Antibodies against p-AKT, p-PRAS40, p-IKK, p-IκB, p-TSC, p-mTOR, p-p70S6K, p-RPS6, p-4E-BP1, pSGK3, AKT, PRAS40, IKK, IκB, mTOR, p70S6K, RPS6, 4E-BP1, GSK3, eIF4G1, and eIF4E were purchased from Cell Signaling Technology. Antibodies against β-actin and α-tubulin were obtained from Santa Cruz Biotechnology. Secondary antibodies were goat anti-rabbit Alexa-680 F(ab')2 and goat anti-mouse IRDye 800 F(ab')2. All antibodies were used according to the suppliers' recommendations.