Cat. No.: HY-159190

HRX-0233

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HRX-0233 is an orally potent MAP2K4 inhibitor. HRX-0233 inhibits the MAP2K4-JNK-JUN signaling pathway, blocks the feedback activation of receptor tyrosine kinases, and sustains the inhibitory effect on KRAS signaling. HRX-0233 exerts synergistic inhibition on the mTORC1 and MAPK pathways. When combined with Ipatasertib (HY-15186) or Sotorasib (HY-114277), it produces synergistic antiproliferative, pro-apoptotic (apoptosis) and antitumor effects, and shows good tolerability in mouse models. HRX-0233 can be used in CRISPR knockout screens to identify vulnerability-related genes. HRX-0233 is applicable to research related to prostate cancer, non-small cell lung cancer and colorectal cancer.

For research use only. We do not sell to patients.

Purity: 98.92%
CAS No.: 2409140-12-9
Formula: C₂₄H₂₁F₂N₅O₃S
Molecular Weight:497.52

Storage:

Powder -20°C, 3 years ; In solvent -80°C, 6 months , -20°C, 1 month

HRX-0233 Chemical Structure

CAS No.: 2409140-12-9

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Top Publications Citing

Use of MCE Products

Fluorescent Dye

Strong Fluorescence Signal / Multi-Disciplinary Applications / High Fluorescence Specificity

Biological Activity
- Description
- IC₅₀ & Target
- In Vitro
- In Vivo
Chemical Information
Solvent & Solubility
- In Vitro
Purity & Documentation
References
Help & FAQs
Classifications
Bioz

Biological Activity

Description

IC₅₀ & Target

MAP2K4

mTOR1

All MEK Isoforms :

All mTOR Isoforms :

In Vitro

Combination treatment with HRX-0233 and Ipatasertib (HY-15186) synergistically reduces cell fitness and inhibits the activities of the mTORC1 and MAPK pathways in AR-negative, PTEN-deficient prostate cancer cells^[1].
HRX-0233 (0-10 μM; 10 to 14 d) exhibits highly synergistic effects with Sotorasib (HY-114277), RMC-6236 (HY-148439), Trametinib (HY-10999) and SCH772984 (HY-50846) in KRAS^G12C-mutant H358, H2122, A549, SW837, HCT116 and DLD1 cancer cells, with the average Bliss synergy score reaching up to 69.89^[2].
HRX-0233 (6 μM; 6-72 h) inhibits the MAP2K4-JNK-JUN signaling pathway, prevents the feedback activation of ERBB2/ERBB3, and sustains the inhibition of downstream RAS signaling pathways (phosphorylated ERK, phosphorylated RSK, phosphorylated S6) in H358, SW837, H2122 and DLD1 cells treated with Sotorasib, RMC-6236 or Trametinib^[2].
HRX-0233 (6 μM) exhibits weak antiproliferative activity, but exerts synergistic effects with Sotorasib or Trametinib in wild-type H358 and SW837 cells; however, its activity is reduced in MAP2K4 knockout cells, indicating that this effect is mainly a target-specific one^[2].
HRX-0233 (6 μM; 3-14 d) acts synergistically with Sotorasib to inhibit proliferation and induce apoptosis in H358 and SW837 cells; it also exerts a synergistic effect with RMC-6236 to suppress proliferation of DLD1 cells^[2].

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

Cell Viability Assay^[2]

Cell Line:

KRAS-mutant non-small cell lung cancer (NSCLC) cell lines H358 (KRASG12C), H2122 (KRASG12C), A549 (KRASG12S) and colorectal cancer (CRC) cell lines SW837 (KRASG12C), HCT116 (KRASG13D), DLD1 (KRASG13D)
Concentration:

0, 2, 4, 6, 8 and 10 μM
Incubation Time:

10 to 14 d, media refreshed every 2 to 3 d
Result:

Exhibited minimal single-agent antiproliferative activity in all tested cell lines.
Produced average Bliss synergy scores of 69.89 (H358), above the 10 threshold for synergy, when combined with sotorasib, with scores also above 10 in H2122 and SW837.
Yielded an average Bliss synergy score of 46.41 (DLD1), with scores above 10 across all tested cell lines, when combined with RMC-6236.
Produced average Bliss synergy scores above 10 in all six cell lines tested when combined with trametinib or SCH772984.

Cell Proliferation Assay^[2]

Cell Line:

KRAS-mutant NSCLC cell lines H358 (KRASG12C), SW837 (KRASG12C) and CRC cell line DLD1 (KRASG13D)
Concentration:

6 μM; 6 μM combined with 50 nM sotorasib (H358, SW837) or 100 nM RMC-6236 (DLD1) (apoptosis readout)
Incubation Time:

10-14 d, media refreshed twice weekly; 72 h (apoptosis readout)
Result:

Had a modest impact on cell proliferation and minimal caspase 3/7 activity when administered alone in all tested cell lines.
Caused sustained suppression of cell proliferation and strong synergistic induction of caspase 3/7 activity in H358 and SW837 cells when combined with sotorasib.
Caused sustained proliferation suppression but only a modest increase in caspase 3/7 activity in DLD1 cells when combined with RMC-6236.

Western Blot Analysis^[2]

Cell Line:

KRAS-mutant NSCLC cell lines H358 (KRASG12C), SW837 (KRASG12C), H2122 (KRASG12C) and CRC cell line DLD1 (KRASG13D)
Concentration:

6 μM; 6 μM combined with 25 nM sotorasib, 100 nM RMC-6236, or trametinib
Incubation Time:

6, 48 and 72 h; 6 and 48 h (with sotorasib); 6 h, 72 h (with RMC-6236); 6 and 72 h (with trametinib)
Result:

Decreased phospho-JUN and total JUN levels in all tested cell lines when administered alone.
Prevented the upregulation of phospho-JUN, phospho-ERBB2, phospho-ERBB3, and total ERBB2/ERBB3 levels induced by single-agent KRAS/MAPK inhibitor treatment at 48 to 72 h when combined with sotorasib, RMC-6236, or trametinib.
Sustained suppression of phospho-ERK, phospho-RSK, and phospho-S6 levels at 48 to 72 h when combined with sotorasib, RMC-6236, or trametinib, whereas single-agent KRAS/MAPK inhibitor treatment showed rebound activation of these signaling markers.
Had no effect on phospho-ERK or phospho-RSK levels when administered alone.

Cell Viability Assay^[2]

Cell Line:

MAP2K4 wild-type and knockout KRASG12C-mutant NSCLC cell line H358 and CRC cell line SW837
Concentration:

6 μM
Incubation Time:

5 d, media refreshed after 2 d
Result:

Induced mild sensitivity in wild-type H358 and SW837 cells, while MAP2K4 knockout cells showed significantly less sensitivity when administered alone.
Enhanced the antiproliferative effect of sotorasib or trametinib in wild-type cells but not in MAP2K4 knockout cells.

In Vivo

HRX-0233 (250 mg/kg; p.o.; daily; up to 60 days) in combination with sotorasib 10 mg/kg induces durable tumor shrinkage and reduces tumor cell proliferation in H358 KRAS^G12C-mutant non-small cell lung cancer xenografts without causing toxicity^[2].
HRX-0233 (250 mg/kg; p.o.; daily; up to 60 days) in combination with trametinib 0.25 mg/kg provides more sustained tumor suppression and reduces tumor cell proliferation in H2122 KRAS^G12C-mutant non-small cell lung cancer xenografts without causing toxicity^[2].

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

Animal Model:

6- to 8-week-old NOD-SCID IL-2Rg(null) (NSG) mice were subcutaneously injected in the right flank with 5 × 10⁶ H358 cells (mixed 1:1 with Matrigel), and treatment was initiated when tumor volumes reached 200-250 mm³^[2]
Dosage:

250 mg/kg (combined with Sotorasib 10 mg/kg)
Administration:

p.o.; daily; up to 60 days
Result:

Showed no effect on tumor growth compared to vehicle.
Induced durable tumor shrinkage (with individual mice showing >30% tumor volume reduction from baseline, meeting RECIST criteria for partial response) over 60 days when combined with sotorasib.
Reduced the percentage of Ki67-positive cells to a significantly lower level than vehicle, HRX-0233 monotherapy, and sotorasib monotherapy (P < 0.0001 vs. vehicle) when combined with sotorasib.
Reduced ERBB2 H-scores compared to vehicle as monotherapy.
Trended toward reversing sotorasib-induced ERBB2 upregulation when co-administered with sotorasib.
Caused no weight loss when combined with sotorasib.

Animal Model:

6- to 8-week-old Balb/c nude mice were subcutaneously injected in the right flank with 5 × 10⁶ H2122 cells (mixed 1:1 with Matrigel), and treatment was initiated when tumor volumes reached approximately 200–250 mm³.^[2]
Dosage:

250 mg/kg (combined with trametinib 0.25 mg/kg)
Administration:

p.o.; daily; up to 60 days
Result:

Monotherapy data was not reported.
Provided more sustained tumor suppression over 60 days compared to trametinib monotherapy when combined with trametinib.
Significantly reduced the percentage of Ki67-positive cells compared to vehicle and trametinib monotherapy when combined with trametinib.
Reduced ERBB2 H-scores compared to vehicle as monotherapy.
Significantly reversed trametinib-induced ERBB2 upregulation when co-administered with trametinib.
Caused no weight loss when combined with trametinib.

Chemical Information

CAS No. 2409140-12-9
Appearance Solid
Molecular Weight 497.52
Formula C₂₄H₂₁F₂N₅O₃S
Color White to off-white
SMILES

O=C(C1=CNC2=NC=C(C3=CN=C(C4CC4)N=C3)C=C21)C5=CC=C(C(NS(=O)(CCC)=O)=C5F)F
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 : 17.5 mg/mL (35.17 mM; Need ultrasonic; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)

View the Complete Stock Solution Preparation Table

Preparing Stock Solutions

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Concentration Solvent Mass

1 mg

5 mg

10 mg

Concentration

Solvent

Mass

1 mM

2.0100 mL

10.0498 mL

20.0997 mL

5 mM

0.4020 mL

2.0100 mL

4.0199 mL

10 mM

0.2010 mL

1.0050 mL

2.0100 mL

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

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

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Purity & Documentation

Select Batch:

Purity: 99.98%

Assay: 99.98%

ee.: 99.98%

Data Sheet (284 KB)
SDS (251 KB)
- English - EN (251 KB)
- Français - FR (251 KB)
- Deutsch - DE (251 KB)
- Norwegian - NO (251 KB)
- Español - ES (251 KB)
- Swedish - SV (251 KB)
- Italian - IT (251 KB)
- Korean - KR (251 KB)
- Portuguese - PT (251 KB)
COA (2659 KB)
Elemental Analysis Report (2659 KB)
HNMR (2659 KB)
CNMR (2659 KB)
RP-HPLC (2659 KB)
NP-HPLC (2659 KB)
MS (2659 KB)
LCMS (2659 KB)
IR (2659 KB)
GC (2659 KB)
OR (2659 KB)
SDS-PAGE (2659 KB)
SEC-HPLC (2659 KB)
Other Report (2659 KB)
Handling Instructions (2659 KB)

References

[1]. Tipayasri P. Development of Rational Combination Therapies for Patients with Metastatic Prostate Cancer and Loss of the PTEN Tumor Suppressor Gene[D]. , 2024.

[2]. Jansen RA, et al. Small-molecule inhibition of MAP2K4 is synergistic with RAS inhibitors in -mutant cancers. Proceedings of the National Academy of Sciences of the United States of America. 2024 Feb 27;121(9):e2319492121. [Content Brief]

Help & FAQs

How should lyophilized recombinant proteins be reconstituted and stored?

1. Before opening the cap, centrifuge the vial at 13000 rpm for 20-30 seconds. This step will ensure that any lyophilized powder that may have adhered to the cap or walls is collected at the bottom of the vial, minimizing the risk of product loss.

Complete Stock Solution Preparation Table

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	2.0100 mL	10.0498 mL	20.0997 mL	50.2492 mL
	5 mM	0.4020 mL	2.0100 mL	4.0199 mL	10.0498 mL
	10 mM	0.2010 mL	1.0050 mL	2.0100 mL	5.0249 mL
	15 mM	0.1340 mL	0.6700 mL	1.3400 mL	3.3499 mL
	20 mM	0.1005 mL	0.5025 mL	1.0050 mL	2.5125 mL
	25 mM	0.0804 mL	0.4020 mL	0.8040 mL	2.0100 mL
	30 mM	0.0670 mL	0.3350 mL	0.6700 mL	1.6750 mL

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HRX-0233

Oxygen Sensing Compound Library

Anti-Lung Cancer Compound Library

Anti-Colorectal Cancer Compound Library

Anti-Prostate Cancer Compound Library

Bioactive Compound Library Max

Kinase Inhibitor Library Mini

MCE Bioactive Compound Library

Bioactive Compound Library

Protein Kinase Compound Library

High-Throughput Bioactive Compound Library

Posttranslational Modification Library

Apoptosis Compound Library

Immunology/Inflammation Compound Library

Kinase Inhibitor Library

MAPK Compound Library

PI3K/Akt/mTOR Compound Library

Stem Cell Signaling Compound Library

Anti-Cancer Compound Library

Autophagy Compound Library

Anti-Aging Compound Library

All MEK Isoforms

All mTOR Isoforms

Biological Activity

Chemical Information

Solvent & Solubility

Purity & Documentation

References

Help & FAQs

Complete Stock Solution Preparation Table

HRX-0233

Oxygen Sensing Compound Library

Anti-Lung Cancer Compound Library

Anti-Colorectal Cancer Compound Library

Anti-Prostate Cancer Compound Library

Bioactive Compound Library Max

Kinase Inhibitor Library Mini

MCE Bioactive Compound Library

Bioactive Compound Library

Protein Kinase Compound Library

High-Throughput Bioactive Compound Library

Posttranslational Modification Library

Apoptosis Compound Library

Immunology/Inflammation Compound Library

Kinase Inhibitor Library

MAPK Compound Library

PI3K/Akt/mTOR Compound Library

Stem Cell Signaling Compound Library

Anti-Cancer Compound Library

Autophagy Compound Library

Anti-Aging Compound Library

All MEK Isoforms

All mTOR Isoforms

Biological Activity

Chemical Information

Solvent & Solubility

Purity & Documentation

References

Help & FAQs

Complete Stock Solution Preparation Table

HRX-0233 Related Classifications

HY-159190 Related Classifications