2. PROTAC MAPK/ERK Pathway
  3. Molecular Glues Raf MEK
  4. NST-628

NST-628 is a brain-permeable MAPK pathway molecule glue that inhibits RAF phosphorylation and MEK activation. NST-628 also binds RAF and prevents the formation of BRAF-CRAF and BRAF-ARAF heterodimers, effectively inhibiting the RAS-MAPK pathway. NST-628 inhibits RAS- and RAF-driven cancers and demonstrated potent inhibition in mutant KRAS, NRAS, BRAF class II/III, and NF1-mutant tumors.

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NST-628 Chemical Structure

NST-628 Chemical Structure

CAS No. : 3002056-30-3

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Based on 1 publication(s) in Google Scholar

NST-628 Related Antibodies

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Description

NST-628 is a brain-permeable MAPK pathway molecule glue that inhibits RAF phosphorylation and MEK activation. NST-628 also binds RAF and prevents the formation of BRAF-CRAF and BRAF-ARAF heterodimers, effectively inhibiting the RAS-MAPK pathway. NST-628 inhibits RAS- and RAF-driven cancers and demonstrated potent inhibition in mutant KRAS, NRAS, BRAF class II/III, and NF1-mutant tumors[1].

In Vitro

NST-628 (100 nM; 2 h) has higher antiproliferative activity in BRAF class II/III mutant cell models compared to other RAF and MEK inhibitors, and it does not promote the formation of BRAF and CRAF heterodimers[2].
NST-628 (4-100 nM; 48 h) increases the levels of early and late apoptotic cells and reduces the number of live 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].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

NST-628 Related Antibodies

Apoptosis Analysis[2]

Cell Line: NRAS mutant IPC-298 and SK-MEL-2, NF1 mutant MeWo, and KRAS mutant HCT116 cell
Concentration: 4, 20, 100 nM
Incubation Time: 48 h
Result: 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).
In Vivo

qd: once daily ; b.i.d: twice daily
NST-628 (p.o.; 3 mg/kg; qd, 5 mg/kg; qd, or 1.5 mg/kg; b.i.d) can significantly slow tumor growth in mouse models with KRAS and NRAS mutations. NST-628 also leads to tumor regressions in the SK-MEL-2-luc model[2].
NST-628 (i.g.; 0.3-3 mg/kg; qd; 18-20 days) inhibites the RAS-MAPK pathway in mice in a dose-dependent manner. NST-628 also exhibites strong antitumor activity in the MeWo-luc model[2].
NST-628 (i.g.; 2 mg/kg; qd; 26 days) slows tumor growth and effectively inhibits the RAS–MAPK pathway in NCI-H23 KRASG12C-mutant lung adenocarcinoma model[2].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model: mouse models with KRAS and NRAS mutations [2]
Dosage: 3 mg/kg; qd, 5 mg/kg; qd, and 1.5 mg/kg; b.i.d
Administration: p.o.
Result: 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)).
Animal Model: NCI-H23 KRASG12C-mutant lung adenocarcinoma model [2]
Dosage: 2 mg/kg; 26 days
Administration: i.g.; qd
Result: The combination of NST-628 and sotorasib resulted in deep tumor regressions that were durable for the 40-day study duration.The combination led to a significant decrease in phospho-ERK levels.
Molecular Weight

488.46

Formula

C22H18F2N4O5S
CAS No.
Appearance

Solid

Color

White to off-white

SMILES

FC1=C(OC2=CC=C(C(C)=C(CC3=C(F)C(NS(NC)(=O)=O)=NC=C3)C(O4)=O)C4=C2)N=CC=C1
Shipping

Room temperature in continental US; may vary elsewhere.
Storage
Powder -20°C 3 years
In solvent -80°C 6 months
-20°C 1 month
Solvent & Solubility
In Vitro: 

DMSO : ≥ 100 mg/mL (204.73 mM; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)

*"≥" means soluble, but saturation unknown.

Preparing
Stock Solutions
Concentration Solvent Mass 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
View the Complete Stock Solution Preparation Table

* Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.

  • Molarity Calculator

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Mass (g) = Concentration (mol/L) × Volume (L) × Molecular Weight (g/mol)

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Concentration (start) × Volume (start) = Concentration (final) × Volume (final)

This equation is commonly abbreviated as: C1V1 = C2V2

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In Vivo:

Select the appropriate dissolution method based on your experimental animal and administration route.

For the following dissolution methods, please ensure to first prepare a clear stock solution using an In Vitro approach and then sequentially add co-solvents:
To ensure reliable experimental results, the clarified stock solution can be appropriately stored based on storage conditions. As for the working solution for in vivo experiments, it is recommended to prepare freshly and use it on the same day.
The percentages shown for the solvents indicate their volumetric ratio in the final prepared solution. If precipitation or phase separation occurs during preparation, heat and/or sonication can be used to aid dissolution.

  • Protocol 1

    Add each solvent one by one:  10% DMSO    40% PEG300    5% Tween-80    45% Saline

    Solubility: ≥ 2.5 mg/mL (5.12 mM); Clear solution

    This protocol yields a clear solution of ≥ 2.5 mg/mL (saturation unknown).

    Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 400 μL PEG300, and mix evenly; then add 50 μL Tween-80 and mix evenly; then add 450 μL Saline to adjust the volume to 1 mL.

    Preparation of Saline: Dissolve 0.9 g sodium chloride in ddH₂O and dilute to 100 mL to obtain a clear Saline solution.
In Vivo Dissolution Calculator
Please enter the basic information of animal experiments:

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Number of animals

Recommended: Prepare an additional quantity of animals to account for potential losses during experiments.
Please enter your animal formula composition:
%
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Recommended: Keep the proportion of DMSO in working solution below 2% if your animal is weak.
The co-solvents required include: DMSO, . All of co-solvents are available by MedChemExpress (MCE). , Tween 80. All of co-solvents are available by MedChemExpress (MCE).
Calculation results:
Working solution concentration: mg/mL
Method for preparing stock solution: mg drug dissolved in μL  DMSO (Stock solution concentration: mg/mL).
The concentration of the stock solution you require exceeds the measured solubility. The following solution is for reference only. If necessary, please contact MedChemExpress (MCE).
Method for preparing in vivo working solution for animal experiments: Take μL DMSO stock solution, add μL . μL , mix evenly, next add μL Tween 80, mix evenly, then add μL Saline.
 If the continuous dosing period exceeds half a month, please choose this protocol carefully.
Please ensure that the stock solution in the first step is dissolved to a clear state, and add co-solvents in sequence. You can use ultrasonic heating (ultrasonic cleaner, recommended frequency 20-40 kHz), vortexing, etc. to assist dissolution.
Purity & Documentation
References

Complete Stock Solution Preparation Table

* Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.

Optional Solvent Concentration Solvent Mass 1 mg 5 mg 10 mg 25 mg
DMSO 1 mM 2.0473 mL 10.2363 mL 20.4725 mL 51.1813 mL
5 mM 0.4095 mL 2.0473 mL 4.0945 mL 10.2363 mL
10 mM 0.2047 mL 1.0236 mL 2.0473 mL 5.1181 mL
15 mM 0.1365 mL 0.6824 mL 1.3648 mL 3.4121 mL
20 mM 0.1024 mL 0.5118 mL 1.0236 mL 2.5591 mL
25 mM 0.0819 mL 0.4095 mL 0.8189 mL 2.0473 mL
30 mM 0.0682 mL 0.3412 mL 0.6824 mL 1.7060 mL
40 mM 0.0512 mL 0.2559 mL 0.5118 mL 1.2795 mL
50 mM 0.0409 mL 0.2047 mL 0.4095 mL 1.0236 mL
60 mM 0.0341 mL 0.1706 mL 0.3412 mL 0.8530 mL
80 mM 0.0256 mL 0.1280 mL 0.2559 mL 0.6398 mL
100 mM 0.0205 mL 0.1024 mL 0.2047 mL 0.5118 mL
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NST-628 Related Classifications

Help & FAQs
  • Do most proteins show cross-species activity?

    Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

Keywords:

NST-6283002056-30-3NST628NST 628Molecular GluesRafMEKRaf kinasesMitogen-activated protein kinase kinaseMAPKKMAP2KInhibitorinhibitorinhibit

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