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| Targets |
NST-628 is a pan-RAF-MEK molecular glue that targets RAF (B-RAF, C-RAF) and MEK (MEK1, MEK2). It binds to RAF and MEK, acting as a molecular glue to stabilize their interaction, but in a non-productive configuration that prevents MEK phosphorylation and activation. This unique mechanism overcomes the limitations of traditional RAS-MAPK inhibitors, which often lose efficacy due to feedback activation or the development of resistance mutations. NST-628 is brain-penetrant and effective against CNS metastases.
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| ln Vitro |
NST-628 (100 nM; 2 h) exhibited higher antiproliferative activity than other RAF and MEK inhibitors in BRAF class II/III mutant cell models and did not promote heterodimer formation of BRAF and CRAF[2]. NST-628 (4-100 nM; 48 h) increased the levels of early and late apoptotic cells and reduced viable cells in a dose-dependent manner in NRAS mutant IPC-298 and SK-MEL-2, NF1 mutant MeWo, and KRAS mutant HCT116 cell lines[2].
In vitro, NST-628 is a potent pan-RAF-MEK molecular glue that prevents the phosphorylation and activation of MEK by RAF, overcoming the limitations of traditional RAS-MAPK inhibitors and leading to deep durable inhibition of the pathway. It has cellular activity across diverse RAS- and RAF-driven cancers. No specific IC50 values are reported. It has broad activity against solid tumor types with alterations in the RAS-MAPK signaling cascade, which is a driver of many cancers. Unlike other inhibitors, NST-628 is a nondegrading molecular glue, meaning it does not promote the degradation of its target proteins but instead locks them in an inactive complex. |
| ln Vivo |
qd: once daily; bid: twice daily NST-628 (po; 3 mg/kg; qd, 5 mg/kg; qd or 1.5 mg/kg; bid) is significant in tumor models with KRAS and NRAS mutations Slows tumor growth. Causes tumor regression in the SK-MEL-2-luc model [2]. NST-628 (ig; 0.3-3 mg/kg; qd; 18-20 days) inhibits the RAS-MAPK pathway in a dose-dependent manner in mice. It has strong anti-tumor activity in the MeWo-luc model [2]. NST-628 (ig; 2 mg/kg; qd; 26 days) slows tumor growth in the NCI-H23-KRASG12C mutant lung adenocarcinoma model. Effectively inhibits the RAS–MAPK pathway [2].
In vivo, NST-628 is an oral, brain-penetrant inhibitor with activity across diverse RAS- and RAF-driven cancers. Treatment leads to broad efficacy with high tolerability and central nervous system activity across multiple RAS- and RAF-driven tumor models. NST-628 is currently being investigated in a Phase 1 clinical trial for patients with MAPK pathway-mutated solid tumors. |
| Enzyme Assay |
The binding of NST-628 to RAF and MEK is measured by cellular thermal shift assays (CETSA) or surface plasmon resonance (SPR) using purified recombinant RAF and MEK proteins. The compound is incubated with the proteins, and the stability of the complex is measured. The “molecular glue” mechanism is confirmed by testing its ability to induce the formation of a RAF-MEK complex in vitro and by cryo-electron microscopy (cryo-EM) to visualize the complex. The IC50 for inhibition of MEK phosphorylation by RAF is measured using standard in vitro kinase assays: purified RAF is incubated with inactive MEK, and the phosphorylation of MEK is measured. The IC50 of NST-628 is calculated from dose-response curves (1-10,000 nM).
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| Cell Assay |
Apoptosis Analysis[2]
Cell Types: NRAS mutant IPC-298 and SK-MEL-2, NF1 mutant MeWo, and KRAS mutant HCT116 cell Concentration: 4, 20, 100 nM Incubation Duration: 48 h Experimental Results: 100 nmol/L NST-628 induced the highest level of apoptosis. Equivalent to the MEK inhibitor Trametinib (HY-10999) and showed greater potency than the MEK inhibitor Cobimetinib (HY-13064), the RAF-MEK inhibitor Avutometinib (HY-18652) and the type II RAF inhibitors Belvarafenib (HY-109080) and Tovorafenib (HY-15246). For cellular assays, cancer cell lines with RAS or RAF mutations (e.g., BRAF V600E, NRAS Q61K, KRAS G12C) are seeded in 96-well plates. Cells are treated with NST-628 at graded concentrations (0.1-10,000 nM) for 72-96 hours. Cell viability is measured by MTT or CellTiter-Glo assays, and the IC50 is calculated for each cell line. Phosphorylation of MEK (pMEK) and ERK (pERK) is measured by Western blot to confirm pathway inhibition. The compound‘s ability to induce the RAF-MEK complex is confirmed by co-immunoprecipitation (co-IP) of RAF and MEK from treated cell lysates. |
| Animal Protocol |
Animal/Disease Models:mouse models with KRAS and NRAS mutations [2]
Doses: 3 mg/kg; qd, 5 mg/kg; qd, and 1.5 mg/kg; b.i.d Route of Administration: p.o. Experimental Results: Significantly inhibited MEK and ERK phosphorylation in tumor tissues. Demonstrated superior anti-tumor efficacy and better tolerability than existing MEK inhibitors (e.g. Cobimetinib (HY-13064)) and RAF inhibitors (e.g. Belvarafenib (HY-109080)). For in vivo evaluation of anti-tumor activity, 6-8-week-old female BALB/c nude mice bearing subcutaneous xenografts of RAS- or RAF-driven cancer cell lines (e.g., A375 for BRAF V600E, HCT116 for KRAS G13D) are used. When tumors reach approximately 100-150 mm3, mice are randomized (n=8-10 per group). NST-628 is administered orally (by gavage) at doses of 10-100 mg/kg once or twice daily for 2-4 weeks. Tumor volumes are measured twice weekly. At the study endpoint, tumors are collected for Western blot analysis of pMEK and pERK. For brain-penetrant activity, orthotopic intracranial xenograft models are used. In Phase 1 clinical trials (NCT06326411), patients with solid tumors harboring MAPK pathway mutations receive oral NST-628 once daily in 28-day cycles. |
| ADME/Pharmacokinetics |
NST-628 (C20H1₈F4N₈O3, MW = 470.39) is a solid powder. For storage, the powder should be kept at -20degC for up to 3 years, sealed and protected from light. For in vitro use, stock solutions in DMSO (10-50 mM) can be stored at -80degC for up to 6 months. For in vivo oral administration, it can be formulated in 10% DMSO / 40% PEG300 / 5% Tween-80 / 45% saline or in 0.5% methylcellulose/0.1% Tween-80. No detailed preclinical PK parameters (Cmax, Tmax, half-life, oral bioavailability) are reported, but the compound is described as orally active and brain-penetrant, with a favorable PK profile.
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| Toxicity/Toxicokinetics |
No specific toxicity data for NST-628 are reported. In preclinical models, NST-628 is described as having high tolerability. In the Phase 1 clinical trial, the primary objective is to assess safety and tolerability; secondary objectives include pharmacokinetics and preliminary efficacy. Common adverse events for MAPK pathway inhibitors include rash, diarrhea, and fatigue, but no specific data are available for NST-628.
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| References |
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| Additional Infomation |
NST-628 is a first-in-class, nondegrading molecular glue that targets the RAF-MEK complex. It was developed by Nurix Therapeutics and is being studied in collaboration with the biopharmaceutical industry. The RAS-MAPK pathway is one of the most frequently altered signaling cascades in human cancer, with activating mutations in KRAS, NRAS, and BRAF found in approximately 30% of all tumors. NST-628's unique mechanism as a molecular glue differentiates it from traditional ATP-competitive inhibitors and MEK inhibitors, potentially offering broader efficacy and a better resistance profile. The compound is currently in Phase 1 clinical trials for the treatment of solid tumors with MAPK pathway alterations (NCT06326411). NST-628 is for research use only; the clinical-grade product is not available for research sale.
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| Molecular Formula |
C22H18F2N4O5S
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|---|---|
| Molecular Weight |
488.46
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| Exact Mass |
488.096
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| CAS # |
3002056-30-3
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| PubChem CID |
169262739
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| Appearance |
Solid powder
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| Density |
1.497±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)
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| Boiling Point |
630.7±65.0 °C(predicted)
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| LogP |
2.7
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
34
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| Complexity |
883
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC1=C(C(OC2=CC(=CC=C21)OC1N=CC=CC=1F)=O)CC1=CC=NC(=C1F)NS(=O)(=O)NC
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| InChi Key |
YQSZJOABXRROQR-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H18F2N4O5S/c1-12-15-6-5-14(32-21-17(23)4-3-8-27-21)11-18(15)33-22(29)16(12)10-13-7-9-26-20(19(13)24)28-34(30,31)25-2/h3-9,11,25H,10H2,1-2H3,(H,26,28)
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| Chemical Name |
3-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-7-(3-fluoropyridin-2-yl)oxy-4-methylchromen-2-one
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ≥ 100 mg/mL (204.73 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.12 mM)(Saturation unknown) in 10% DMSO 40% PEG300 5% Tween-80 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution, add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix well; then add 50 μL Tween-80 to the above system and mix well; then add 450 μL saline to make it 1 mL. *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0473 mL | 10.2363 mL | 20.4725 mL | |
| 5 mM | 0.4095 mL | 2.0473 mL | 4.0945 mL | |
| 10 mM | 0.2047 mL | 1.0236 mL | 2.0473 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Link: https://clinicaltrials.gov/ct2/show/NCT06326411
Conditions:Oncology|MEK Mutation|RAF Gene Mutation|Ras (KRAS or NRAS) Gene Mutation|Melanoma|NSCLC|Glioma|Solid Tumor, Adult|MAPK Pathway Gene MutationProducts are for research use only; We do not sell to patients
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