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SF1126 Sale

(Synonyms: N2-[1,4-二氧代-4-[[4-(4-氧代-8-苯基-4H-1-苯并吡喃-2-基)吗啉-4-基]甲氧基]丁基]-L-精氨酰甘氨酰-L-ALPHA-天冬氨酰-L-丝氨酸内盐) 目录号 : GC37633

SF1126 是临床相关的双重 PI3K/BRD4 泛抑制剂,具有抗肿瘤和抗血管生成活性。SF1126 是 RGDS-缀合的 LY294002 前药,其设计为表现出增加的溶解度并与肿瘤区室内的特定整联蛋白结合。SF1126 诱导细胞凋亡 (apoptosis)。

SF1126 Chemical Structure

Cas No.:936487-67-1

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产品描述

SF1126 is a clinically relevant pan and dual first-in-class PI3K/BRD4 inhibitor, has antitumor and anti-angiogenic activity. SF1126 is an RGDS-conjugated LY294002 prodrug, which is designed to exhibit increased solubility and bind to specific integrins within the tumor compartment. SF1126 induces cell apoptosis[1]. PI3K/BRD4[1]

SF1126 (0-6 µM; 48 hours) inhibits Hep3B, HepG2, SK-Hep1, and Huh7 cells proliferation with IC50s of 5.05, 6.89, 3.14, and 2.14 µM, respectively[1].SF1126 (1-10 µM; 24 hours) results in cell-cycle arrest with a proportional increase in G0-G1 and a decrease in the number of cells in the S-phase in Hep 3B, Hep G2, SK-Hep1, and Huh7 cells[1].SF1126 (0.5-2.5 µM; pre-30 minutes) and sorafenib suggests that combined treatment of SF1126 and sorafenib blocks multiple key enzymes in PI3K/AKT/mTOR and Ras/Raf/MAPK pathway[1]. Cell Viability Assay[1] Cell Line: Hep3B, HepG2, SK-Hep1, and Huh7 cells

[1]. Garlich JR, et al. A vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug, SF1126, with antitumor and antiangiogenic activity. Cancer Res. 2008 Jan 1;68(1):206-15.

Chemical Properties

Cas No. 936487-67-1 SDF
别名 N2-[1,4-二氧代-4-[[4-(4-氧代-8-苯基-4H-1-苯并吡喃-2-基)吗啉-4-基]甲氧基]丁基]-L-精氨酰甘氨酰-L-ALPHA-天冬氨酰-L-丝氨酸内盐
Canonical SMILES N=C(N)NCCC[C@H](NC(CCC(OC[N+]1(CCOCC1)C(OC(C2=CC=C3)=C3C4=CC=CC=C4)=CC2=O)=O)=O)C(NCC(N[C@@H](CC([O-])=O)C(N[C@@H](CO)C(O)=O)=O)=O)=O
分子式 C39H48N8O14 分子量 852.84
溶解度 Soluble in DMSO 储存条件 Store at -20°C
General tips 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液;一旦配成溶液,请分装保存,避免反复冻融造成的产品失效。
储备液的保存方式和期限:-80°C 储存时,请在 6 个月内使用,-20°C 储存时,请在 1 个月内使用。
为了提高溶解度,请将管子加热至37℃,然后在超声波浴中震荡一段时间。
Shipping Condition 评估样品解决方案:配备蓝冰进行发货。所有其他可用尺寸:配备RT,或根据请求配备蓝冰。

溶解性数据

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1 mg 5 mg 10 mg
1 mM 1.1726 mL 5.8628 mL 11.7255 mL
5 mM 0.2345 mL 1.1726 mL 2.3451 mL
10 mM 0.1173 mL 0.5863 mL 1.1726 mL
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Research Update

Dual PI3K-BRD4 Inhibitor SF1126 Inhibits Colorectal Cancer Cell Growth in Vitro and in Vivo

Cell Physiol Biochem 2019;52(4):758-768.PMID:30933440DOI:10.33594/000000053.

Background/aims: Bromodomain-containing protein 4 (BRD4) and phosphatidylinositol 3-kinase (PI3K) are key oncogenic cascades in colorectal cancer (CRC). SF1126 is a novel and potent PI3K-BRD4 dual inhibitor. Methods: CRC cells and human colon epithelial cells were treated with SF1126. Cell survival was tested by MTT and soft agar colony formation assays. Cell proliferation was tested by BrdU ELISA method. Cell apoptosis was tested by a TUNEL staining method and Histone DNA ELISA. Western blotting was utilized to test the signaling proteins. A HT-29 xenograft mice model was established to study the anti-tumor activity of SF1126 in vivo. Results: SF1126 potently inhibited the survival, proliferation, and progression of the cell cycle in an established CRC cell line (HT-29) and primary human colon cancer cells. Significant activation of apoptosis was detected in SF1126-treated CRC cells. In CRC cells, SF1126 blocked Akt-mammalian target of rapamycin (mTOR) complex1/2 signaling and downregulated BRD4 target proteins (Myc and cyclin D1). Further studies showed that SF1126 activated p38 signaling in CRC cells. In contrast, the p38 inhibitors or p38 short hairpin RNA inhibited SF1126-induced cytotoxicity and apoptosis in CRC cells. In vivo, subcutaneous administration of SF1126 significantly inhibited HT-29 xenograft tumor growth in nude mice. Conclusion: SF1126 inhibits CRC cell growth possibly by targeting PI3K-Akt-mTOR, BRD4, and p38 signaling.

Augmented Antitumor Activity for Novel Dual PI3K/BDR4 Inhibitors, SF2523 and SF1126 in Ewing Sarcoma

J Pediatr Hematol Oncol 2021 Apr 1;43(3):e304-e311.PMID:33480647DOI:10.1097/MPH.0000000000002054.

Ewing sarcoma (ES) is the second most common pediatric bone cancer. Despite recent advances in the treatment, patients with metastatic tumors have dismal prognosis and hence novel therapies are urgently needed to combat this cancer. A recent study has shown that phosphoinositide-3 kinase (PI3K) inhibitors can synergistically increase sensitivity to bromodomain and extraterminal domain inhibitors in ES cells and therefore combined inhibition of PI3K and bromodomain and extraterminal domain bromodomain proteins might provide benefit in this cancer. Herein, we have investigated the efficacy of dual PI3K/BRD4 inhibitors, SF2523 and SF1126, for their antitumor activity in ES cell lines. The effect of SF1126 and SF2523 on cell viability and PI3K signaling was assessed on a panel of human ES cell lines. To evaluate the antitumor activity of SF1126, A673 cells were injected intrafemorally into RAG-2-/- mice and treated with 50 mg/kg SF1126 6 days per week, for 30 days. Both SF1126 and SF2523 decreased cell survival and inhibited phosphorylation of AKT in human ES cell lines. In vivo, SF1126 showed a significant reduction in tumor volume. These results suggest that dual PI3K/BRD4 inhibitor, SF1126, has antitumor activity in ES models.

Pan-PI-3 kinase inhibitor SF1126 shows antitumor and antiangiogenic activity in renal cell carcinoma

Cancer Chemother Pharmacol 2015 Mar;75(3):595-608.PMID:25578041DOI:10.1007/s00280-014-2639-x.

Purpose: SF1126 is a vascular-targeted pan-PI-3K inhibitor prodrug with antitumor and antiangiogenic activity and has completed phase I clinical trial in solid tumors and B-cell malignancies. In this study, we investigated the effect of SF1126 on hypoxic HIF-1α/HIF-2α stability as well as on antitumor and/or antiangiogenic activity in renal cell carcinoma (RCC) models in vitro and in vivo. Methods: The effect of SF1126 on hypoxic HIF-1α/HIF-2α protein stability, antitumor and antiangiogenic activity was studied on VHL-null (786-0) and VHL-WT (Caki) RCC cells. Results: Our data demonstrate that SF1126 treatment abrogates the stabilization of HIF-2α in 786-0 (VHL-mutated) RCC cell line under normoxic and hypoxic conditions. Similarly, hypoxic stabilization of HIF-1α and its activity were also suppressed following SF1126 treatment in Caki cell line (VHL-WT). Herein, we provide mechanistic evidence that HIF-2α can be degraded in cytoplasm under hypoxic conditions via the 26S proteasome and that MDM2 is the E3 ligase which induces the hypoxic degradation of HIF-2α in PI-3K-dependent manner in VHL-deficient RCC cells. Moreover, SF1126 administered to RCC-xenografted mice at 25 mg/kg/dose subcutaneously three times per week for 3 weeks results in marked inhibition of tumor growth (>90 % inhibition) (P < 0.05). Consistent with SF1126 treatment's effects on HIF-1α/HIF-2α, microvessel density analysis of Caki and 786-0 tumor tissues demonstrated that SF1126 has potent antiangiogenic activity in vivo. Finally, SF1126 caused a profound inhibition of integrin-mediated migration and blocked the integrin-induced conversion of GDP-Rac1 to its GTP-bound active state. Conclusions: These results validate the in vivo efficacy of SF1126 as a clinically viable antiangiogenic, pan-PI-3K inhibitor prodrug for phase II clinical trials in the treatment of RCC.

Combination of SF1126 and gefitinib induces apoptosis of triple-negative breast cancer cells through the PI3K/AKT-mTOR pathway

Anticancer Drugs 2015 Apr;26(4):422-7.PMID:25588160DOI:10.1097/CAD.0000000000000202.

To investigate the apoptotic mechanism of triple-negative breast cancer (TNBC) cells induced by gefitinib and PI3K inhibitor SF1126. MDA-MB-231, MDA-MB-436, and MCF-7 cells were incubated with 0.1 μmol/l gefitinib, 1 μmol/l gefitinib, 10 μmol/l gefitinib, 1 μmol/l SF1126, 0.1 μmol/l gefitinib+1 μmol/l SF1126, 1 μmol/l gefitinib+1 μmol/l SF1126, and 10 μmol/l gefitinib+1 μmol/l SF1126. Then, cell viability and survival were determined using an 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay and Hoechst staining. The apoptosis-related factors and phosphoinositide-3-kinase/protein kinase B, the mammalian target of rapamycin (PI3K/AKT-mTOR) signaling pathway-related factors were detected by western blot. For TNBC cells, cell viability or survival was not significantly inhibited by gefitinib or SF1126 alone; however, marked cell apoptosis was noted in the gefitinib and SF1126 combination groups, and this effect was dose dependent. Also, the expressions of apoptosis markers, such as cleaved caspase-3, Bcl-2/Bax, were altered by the gefitinib and SF1126 combination. Moreover, phosphorylated AKT (p-AKT) and 70 kDa ribosomal protein S6-kinase (p-p70S6K) were also inhibited by the gefitinib and SF1126 combination, which may be responsible for the apoptosis. Gefitinib combined with SF1126 could induce cell apoptosis in TNBC cells and this effect was mediated through the EGFR-PI3K-AKT-mTOR-p70S6K pathway. Our studies have set the stage for future clinical trials of TNBC therapy by the combination of gefitinib and SF1126.

An integrin-targeted, pan-isoform, phosphoinositide-3 kinase inhibitor, SF1126, has activity against multiple myeloma in vivo

Cancer Chemother Pharmacol 2013 Apr;71(4):867-81.PMID:23355037DOI:10.1007/s00280-013-2078-0.

Purpose: Multiple reports point to an important role for the phosphoinositide-3 kinase (PI3K) and AKT signaling pathways in tumor survival and chemoresistance in multiple myeloma (MM). The goals of our study were: (1) to generate the preclinical results necessary to justify a Phase I clinical trial of SF1126 in hematopoietic malignancies including MM and (2) to begin combining pan-PI3K inhibitors with other agents to augment antitumor activity of this class of agent in preparation for combination therapy in Phase I/II trials. Methods: We determined the in vitro activity of SF1126 with 16 human MM cell lines. In vivo tumor growth suppression was determined with human myeloma (MM.1R) xenografts in athymic mice. In addition, we provide evidence that SF1126 has pharmacodynamic activity in the treatment of patients with MM. Results: SF1126 was cytotoxic to all tested MM lines, and potency was augmented by the addition of bortezomib. SF1126 affected MM.1R cell line signaling in vitro, inhibiting phospho-AKT, phospho-ERK, and the hypoxic stabilization of HIF1α. Tumor growth was 94 % inhibited, with a marked decrease in both cellular proliferation (PCNA immunostaining) and angiogenesis (tumor microvessel density via CD31 immunostaining). Our clinical results demonstrate pharmacodynamic knockdown of p-AKT in primary patient-derived MM tumor cells in vivo. Conclusions: Our results establish three important points: (1) SF1126, a pan-PI3K inhibitor has potent antitumor activity against MM in vitro and in vivo, (2) SF1126 displays augmented antimyeloma activity when combined with proteasome inhibitor, bortezomib/Velcade(®), and (3) SF1126 blocks the IGF-1-induced activation of AKT in primary MM tumor cells isolated from SF1126-treated patients The results support the ongoing early Phase I clinical trial in MM and suggest a future Phase I trial in combination with bortezomib in hematopoietic malignancies.