2. Others MAPK/ERK Pathway GPCR/G Protein
  3. Drug Intermediate Ras
  4. ADT-1004

ADT-1004 is an orally active prodrug of ADT-007 (HY-157887). ADT-007 is a reversible, highly potent and selective pan-RAS inhibitor that binds to the nucleotide-free conformation of RAS proteins and blocks their GTP activation, thereby inhibiting the downstream MAPK and AKT signaling pathways. ADT-1004 can be used for the research of pancreatic ductal adenocarcinoma.

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

ADT-1004

ADT-1004 Chemical Structure

CAS No. : 1945941-72-9

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Based on 1 publication(s) in Google Scholar

ADT-1004 Related Antibodies

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Description

ADT-1004 is an orally active prodrug of ADT-007 (HY-157887). ADT-007 is a reversible, highly potent and selective pan-RAS inhibitor that binds to the nucleotide-free conformation of RAS proteins and blocks their GTP activation, thereby inhibiting the downstream MAPK and AKT signaling pathways. ADT-1004 can be used for the research of pancreatic ductal adenocarcinoma[1].

In Vitro

ADT-007 (0.1-600 nM; 3 days) potently inhibits the viability of KRASG12C mutant MIA PaCa-2 PDAC cells in vitro with an IC50 of 3.06 nM[1].
ADT-007 (0.1-600 nM; 3 days) potently inhibits the viability of sotorasib/adagrasib-resistant KRASG12C mutant MIA-AMG-R PDAC cells in vitro with an IC50 of 15.59 nM[1].
ADT-007 (5-10 nM; 2 weeks) potently inhibits colony formation of KRASG12C mutant MIA PaCa-2 PDAC cells in vitro at concentrations as low as 5 nM[1].
ADT-007 (5-10 nM; 2 weeks) potently inhibits colony formation of sotorasib/adagrasib-resistant KRASG12C mutant MIA-AMG-R PDAC cells in vitro at concentrations as low as 5 nM[1].
ADT-007 retains growth inhibitory activity against MRTX1133-resistant KRASG12D mutant AsPC-1 PDAC cells in vitro[1].

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

ADT-1004 Related Antibodies
In Vivo

ADT-1004 (10-50 mg/kg; p.o.; once daily or twice daily, 5 days a week for 27 consecutive days) exhibits significant anti-tumor activity in orthotopic mouse models of pancreatic ductal adenocarcinoma (PDAC) (KPC-luc and 2838c3-luc)[1].
ADT-1004 (40 mg/kg; p.o.; once daily, 5 days per week for 28 consecutive days) inhibits tumor growth, reduces the levels of activated RAS and pERK, and shifts the macrophage population in the tumor microenvironment toward the M1 phenotype in orthotopic KRASG12D-mutant pancreatic ductal adenocarcinoma in C57BL/6J mice[1].
ADT-1004 (40 mg/kg; p.o.; once daily, 5 times per week) inhibits tumor growth, attenuates pERK signaling, reduces stromal αSMA expression, and decreases tumor cell proliferation in subcutaneous KRASG12D, KRASG12C, KRASG12V, and KRASG13Q pancreatic ductal adenocarcinoma PDX models in NSG mice[1].
ADT-1004 (40 mg/kg; p.o.; once daily, 5 days per week for 31 days) inhibits tumor growth of both parental and Sotorasib/Adagrasib-resistant KRASG12C-mutant pancreatic ductal adenocarcinoma in NSG mice and reduces their pERK levels[1].

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

Animal Model: C57BL/6J[1]
Dosage: 10 mg/kg; 20 mg/kg; 30 mg/kg; 40 mg/kg; 50 mg/kg
Administration: p.o.; once daily; 5x/week; 27 days
Result: Reduced tumor bioluminescence relative to vehicle across all doses.
Produced statistically significant reductions in tumor weight compared to vehicle or 10 mg/kg dose at 20-50 mg/kg.
Reached average plasma concentrations of active metabolite ADT-007 of 3.4 nM (20 mg/kg), 5.7 nM (30 mg/kg), 31.2 nM (40 mg/kg), and 54.1 nM (50 mg/kg) 6 hours after final dose.
Showed no significant body weight differences between treated and vehicle groups.
Animal Model: C57BL/6J[1]
Dosage: 40 mg/kg
Administration: p.o.; once daily; 5x/week; 27 days
Result: Reduced tumor bioluminescence and tumor weight significantly relative to vehicle.
Reduced activated RAS-GTP levels significantly and reduced pERK levels by ~60% relative to vehicle in tumors.
Reduced density of F4/80+ macrophages, reduced CD206 (M2 marker) expression on F4/80+ macrophages, reduced MHCII expression on F4/80+ macrophages, and increased M1/M2 macrophage ratio in the tumor microenvironment.
Animal Model: C57BL/6J (female)[1]
Dosage: 20 mg/kg (QD); 20 mg/kg (BID); 40 mg/kg (QD)
Administration: p.o.; 5x/week
Result: Produced comparable, significant reductions in tumor bioluminescence and tumor weight relative to vehicle across all dosing regimens.
Showed no significant body weight differences from vehicle.
Reduced activated RAS-GTP levels by ~70% and pERK levels by ~60% relative to vehicle in tumors.
Increased density of CD4+ T cells, CD4+ FoxP3+ Tregs, CD4+ PD-1+ T cells, CD4+ CTLA4+ T cells, CD8+ T cells, CD8+ PD-1+ T cells, CD8+ CTLA4+ T cells, and CD8+ PD-1+ CTLA4+ LAG3+ CD44+ exhausted T cells in the tumor microenvironment.
Increased density of CD103+ dendritic cells, cDC1 dendritic cells, F4/80+ Ly6G+ granulocytic MDSCs, and F4/80+ macrophages with increased MHCII expression, while reducing CD206 expression on F4/80+ macrophages.
Animal Model: NSG[1]
Dosage: 40 mg/kg
Administration: p.o.; once daily; 5x/week
Result: Reduced tumor volume and final tumor weight significantly in all four KRAS-mutant (G12D, G12C, G12V, G13Q) PDX models relative to vehicle.
Showed no significant body weight changes from vehicle.
Reduced pERK levels, αSMA expression, and Ki-67 proliferation marker levels significantly in treated tumors relative to vehicle via IHC analysis.\nReduced tumor volume and final tumor weight significantly in parental KRASG12C MIA PaCa-2 tumors relative to vehicle, with significant reduction in pERK levels.
Produced dramatic reduction in tumor volume and final tumor weight in sotorasib/adagrasib-resistant KRASG12C MIA-AMG-R tumors relative to vehicle, with significant reduction in pERK levels; sotorasib and adagrasib showed no efficacy in this resistant model.
Showed no significant body weight changes between treated and vehicle groups.
Animal Model: NSG (male)[1]
Dosage: 40 mg/kg
Administration: p.o.; once daily; 5x/week; 31 days
Result: Did not significantly affect tumor volume or final tumor weight relative to vehicle.
Showed no significant body weight changes from vehicle.
Molecular Weight

589.65

Formula

C33H36FN3O6
CAS No.
Appearance

Solid

Color

Light yellow to yellow

SMILES

O=C(NCC1=CC=CO1)CC2=C(C)/C(C3=CC=C(F)C=C32)=C/C4=CC(OC)=C(C(OC)=C4)OC(NC5CCN(CC5)C)=O
Shipping

Room temperature in continental US; may vary elsewhere.
Storage
Powder -20°C 3 years
4°C 2 years
In solvent -80°C 6 months
-20°C 1 month
Solvent & Solubility
In Vitro: 

DMSO : 4.17 mg/mL (7.07 mM; Need ultrasonic; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)

Preparing
Stock Solutions
Concentration Solvent Mass 1 mg 5 mg 10 mg
1 mM 1.6959 mL 8.4796 mL 16.9592 mL
5 mM 0.3392 mL 1.6959 mL 3.3918 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.

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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 1.6959 mL 8.4796 mL 16.9592 mL 42.3980 mL
5 mM 0.3392 mL 1.6959 mL 3.3918 mL 8.4796 mL
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  • 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:

ADT-10041945941-72-9ADT1004ADT 1004Drug IntermediateRasDrug Iintermediatemutant RASCD8+ T cellsKRAS mutationsMHCII+ M1 macrophagesMIA PaCa-2 PDAC cellsCD4+ T cellsdendritic cellswild-type RASpancreatic ductal adenocarcinomaMAPK pathwayInhibitorinhibitorinhibit

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