SF1126

Summary

SF1126 is an investigational, cRGD‑PEGylated peptidomimetic pro‑drug that delivers the pan‑phosphoinositide‑3‑kinase (PI3K) inhibitor LY294002. It targets the PI3K/Akt/mTOR signaling axis and, in later studies, also inhibits the bromodomain protein BRD4. Developed for oncology, it has been examined in early‑phase trials for solid tumours, B‑cell malignancies and multiple myeloma, and in pre‑clinical models of colorectal cancer, neuroblastoma, and Ewing sarcoma.

Mechanism of Action

SF1126 is a water‑soluble pro‑drug that, after intravenous administration, is converted to LY294002, a pan‑class I PI3K inhibitor. By blocking PI3K it suppresses downstream Akt and mTORC1/2 activity, reducing proliferation, survival and angiogenic signals. The cRGD moiety directs the compound to integrin‑expressing tumour cells, enhancing uptake. In later investigations SF1126 also binds the bromodomain protein BRD4, down‑regulating MYC and cyclin D1, and engages p38 MAPK pathways that contribute to apoptosis in colorectal cancer cells.

What the Research Shows

Pre‑clinical work demonstrates that SF1126 kills multiple myeloma cell lines, augments bortezomib activity, and inhibits tumor growth (>90% reduction) in MM xenografts while lowering phospho‑AKT, phospho‑ERK and HIF‑1α. Similar pan‑PI3K inhibition reduces Akt‑MDM2‑survivin signaling in neuroblastoma, synergises with doxorubicin, and shrinks neuroblastoma xenografts. In colorectal cancer, SF1126 blocks PI3K‑Akt‑mTOR and BRD4 targets, activates p38, and curtails HT‑29 tumour growth in mice. Ewing sarcoma cell viability falls with AKT dephosphorylation, and intrafemoral mouse models show reduced tumour volume. A first‑in‑human Phase I trial in 44 patients with advanced solid tumours or B‑cell malignancies reported dose‑proportional exposure, mainly grade 1‑2 toxicities, one diarrhoea DLT, and stable disease in 58% of evaluable patients, with pharmacodynamic evidence of p‑AKT reduction.

Reported Benefits

Evidence from animal models indicates that SF1126 can markedly inhibit tumour growth in multiple myeloma, neuroblastoma, colorectal cancer and Ewing sarcoma, often enhancing the efficacy of standard agents such as bortezomib or doxorubicin. Early clinical data show that the drug is generally well tolerated and can achieve disease stabilisation in a majority of heavily pre‑treated patients, suggesting potential utility as a single agent or in combination regimens targeting PI3K‑dependent cancers.

Limitations of the Evidence

The clinical experience is limited to a single Phase I study with modest sample size and no objective tumour regressions reported; the best outcome was disease stabilisation. Long‑term safety, optimal dosing and efficacy in specific tumour types remain undefined. Pre‑clinical synergy findings have not yet been validated in patients, and the dual PI3K/BRD4 activity, while promising, is based on in‑vitro and mouse data only.

Safety Considerations

In the Phase I trial, most adverse events were grade 1‑2, including fatigue, nausea and transient laboratory changes. One patient experienced a dose‑limiting diarrhoea at 180 mg/m²; no other grade 3 or higher toxicities were reported, and a maximum administered dose of 1110 mg/m² was tolerated. Pharmacodynamic monitoring showed reduced p‑AKT in circulating tumour cells, indicating target engagement. As with other PI3K inhibitors, clinicians should watch for hyperglycaemia, rash or gastrointestinal upset, although these were not prominent in the reported cohort.

How It Is Administered

SF1126 is administered intravenously as a pro‑drug infusion on days 1 and 4 of each week within a 28‑day cycle. The formulation is a water‑soluble PEGylated peptide that is converted in vivo to the active LY294002. Pre‑clinical studies also used subcutaneous injection in mice, but human use to date has been limited to the intravenous route.

Routes of Administration

Goals & Uses

• Treatment of B-cell malignancies (CLL, B-cell NHL)Oncology / HematologyLow
• Tumor growth inhibitionOncologyModerate
• Treatment of advanced solid tumorsOncologyLow
• PI3K/Akt/mTOR pathway blockadeSignal Transduction InhibitionModerate
• Tumor angiogenesis inhibitionOncology / AntiangiogenicModerate

Contraindications

• Severe hepatic impairmentOrganModerateLiver function concerns
• Known hypersensitivity to peptide or PEG componentsAllergyModerate
• Known hypersensitivity to LY294002 or RGDS componentsAllergyHigh
• Active uncontrolled infectionInfectious DiseaseModerate

Adverse Effects

• HyperglycemiaMetabolicCommonAbnormally high blood glucose
• ThrombocytopeniaHematologicUncommonLow platelet count
• Nausea/vomitingGastrointestinalCommon
• Infusion‑related reactionsGeneralCommon
• NauseaGastrointestinalCommonFeeling of sickness or urge to vomit
• FatigueGeneralCommonLow energy or tiredness
• Elevated liver enzymes (transaminases)HepaticUncommon
• Infusion-related reactionsHypersensitivityUncommon
• DiarrheaGastrointestinalUncommonLoose or frequent stools

Drug Interactions

• CYP3A4 inhibitorsModerate
• Antidiabetic agents (insulin, metformin)Moderate
• Anticoagulants (warfarin, heparin)Moderate
• CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin)Moderate

Population Constraints

• PregnancyReproductive SafetyAbsolute
• Pediatric patientsAgeRelative
• Patients with diabetes mellitusMetabolicRelative
• PediatricsAgeRelative

Regulatory Status

• European UnionUnknownNo marketing authorization; clinical studies ongoing.
• United StatesInvestigationalIND; Phase I/II trials in solid tumors.
• United KingdomUnknownNo MHRA approval documented.

IND status in the United States; no approved indication in any jurisdiction.

Evidence & Sources

• PI3 kinase/AKT pathway as a therapeutic target in multiple myeloma
  Journal ArticleModerateHarvey RD, Lonial S2007-01-01T00:00:00.000000Z
• Phase I pharmacokinetic and pharmacodynamic study of the pan-PI3K/mTORC vascular targeted pro-drug SF1126 in patients with advanced solid tumours and B-cell malignancies
  Journal ArticleModerateMahadevan D, et al.2012-01-01T00:00:00.000000Z
• An integrin-targeted, pan-isoform, phosphoinositide-3 kinase inhibitor, SF1126, has activity against multiple myeloma in vivo
  Journal ArticleModerateDe P, et al.2013-01-01T00:00:00.000000Z
• Dual PI3K-BRD4 Inhibitor SF1126 Inhibits Colorectal Cancer Cell Growth in Vitro and in Vivo
  Journal ArticleLowQin AC, et al.2019-01-01T00:00:00.000000Z
• The PI-3 kinase-Akt-MDM2-survivin signaling axis in high-risk neuroblastoma: a target for PI-3 kinase inhibitor intervention
  Journal ArticleLowPeirce SK, et al.2011-01-01T00:00:00.000000Z
• Augmented Antitumor Activity for Novel Dual PI3K/BDR4 Inhibitors, SF2523 and SF1126 in Ewing Sarcoma
  Journal ArticleLowGoldin AN, et al.2021-01-01T00:00:00.000000Z

Frequently Asked Questions