2. Cell Cycle/DNA Damage
  3. PERK
  4. HC-5404-Fu

HC-5404-Fu is an orally active PERK inhibitor with an IC50 of 0.001 μM against human PERK. HC-5404-Fu blocks PERK activation induced by VEGFR-TKI and disrupts the adaptive stress response triggered by VEGFR-TKI. HC-5404-Fu enhances anti-angiogenic effects by inhibiting newly formed and mature tumor blood vessels in renal cell carcinoma models. HC-5404-Fu can be used in research related to renal cell carcinoma.

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HC-5404-Fu

HC-5404-Fu Chemical Structure

CAS No. : 3034479-99-4

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Based on 1 publication(s) in Google Scholar

HC-5404-Fu Related Antibodies

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Description

HC-5404-Fu is an orally active PERK inhibitor with an IC50 of 0.001 μM against human PERK. HC-5404-Fu blocks PERK activation induced by VEGFR-TKI and disrupts the adaptive stress response triggered by VEGFR-TKI. HC-5404-Fu enhances anti-angiogenic effects by inhibiting newly formed and mature tumor blood vessels in renal cell carcinoma models. HC-5404-Fu can be used in research related to renal cell carcinoma[1].

In Vitro

HC-5404-Fu (1 nmol/L) potently and selectively inhibits recombinant PERK kinase activity in a cell-free biochemical assay with an IC50 of 1 nmol/L, exhibiting >2,000-fold selectivity over other ISR kinases[1].
HC-5404-Fu (100-10,000 nmol/L) demonstrates high kinome selectivity in a cell-free binding assay, with no off-target kinase interactions at 100 nmol/L and only limited interactions at concentrations ≥1,000 nmol/L[1].
HC-5404-Fu (1.5 nmol/L-10 μmol/L; 30-minute pretreatment, 4-hour co-incubation with tunicamycin) inhibits ER stress-mediated PERK activation and downstream ATF4 induction in HEK-293 cells with IC50 values of 23 nmol/L (pPERK) and 88 nmol/L (ATF4)[1].

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

HC-5404-Fu Related Antibodies

Western Blot Analysis[1]

Cell Line: HEK-293 cells
Concentration: 1.5 nmol/L-10 μmol/L
Incubation Time: 30-minute pretreatment; 4-hour co-incubation with tunicamycin
Result: Inhibited tunicamycin-induced PERK autophosphorylation (pPERK Thr982) with an IC50 of 23 nmol/L.
Inhibited tunicamycin-induced ATF4 protein accumulation with an IC50 of 88 nmol/L.
In Vivo

HC-5404-Fu (3-100 mg/kg; p.o.; single dose) administered as a single oral dose induces rapid, dose-dependent inhibition of pPERK in mouse pancreas and tumor tissue, with 30 mg/kg achieving 90% pPERK inhibition in 786-O tumors at 1 hour[1].
HC-5404-Fu (3-30 mg/kg; p.o.; twice-a-day; 28 days) administered orally twice-a-day exerts dose-dependent single-agent antitumor activity in 786-O RCC xenografts, with 30 mg/kg twice-a-day achieving 48% TGI[1].
HC-5404-Fu (30-100 mg/kg; p.o.; twice-a-day; 48 days) administered orally twice-a-day exerts single-agent antitumor activity in Capan-2 pancreatic cancer xenografts, with 30 mg/kg twice-a-day achieving 50% TGI, a comparable effect to the higher 100 mg/kg twice-a-day dose[1].
HC-5404-Fu (30 mg/kg; p.o.; twice-a-day; 28 days) administered at 30 mg/kg orally twice-a-day enhances the antitumor efficacy of multiple VEGFR-TKI in 786-O RCC xenografts, inhibiting VEGFR-TKI-induced PERK activation and driving tumor regression when combined with axitinib or cabozantinib[1].
HC-5404-Fu (30 mg/kg; p.o.; twice-a-day; 28 to 30 days) administered at 30 mg/kg orally twice-a-day enhances the antitumor efficacy of sunitinib in both VHL-mutant (A-498) and VHL-wildtype (Caki-1) RCC xenografts, driving 22% tumor regression in A-498 models and 47% TGI in Caki-1 models[1].
HC-5404-Fu (30 mg/kg; p.o.; twice-a-day; 28 days) administered at 30 mg/kg orally twice-a-day enhances the antitumor efficacy of axitinib across a panel of 18 RCC PDX models, increasing the number of partial responses from 2 to 9 models, with 3 of 6 VHL-wildtype models showing improved response to the combination[1].
HC-5404-Fu (30 mg/kg; p.o.; twice-a-day; 28 days) administered at 30 mg/kg orally twice-a-day enhances the antitumor efficacy of the anti-VEGFR-2 antibody DC-101 in 786-O and A-498 RCC xenografts, achieving 82% and 78% TGI, respectively[1].
HC-5404-Fu (30 mg/kg; p.o.; twice-a-day; 28 days) administered at 30 mg/kg orally twice-a-day induces tumor regression (20% relative to baseline) when combined with axitinib in 786-O RCC xenografts that have progressed on axitinib monotherapy, while single-agent HC-5404 achieves 47% tumor growth inhibition relative to vehicle[1].

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

Animal Model: athymic nude-Foxn1nu (6- to 8-week-old female; subcutaneously injected with 1×106 T-HEP3-PERK PERK-overexpressing human squamous cell carcinoma cells)[1]
Dosage: 3 mg/kg; 30 mg/kg; 100 mg/kg
Administration: p.o.; single dose
Result: Induced 90% inhibition of pPERK in mouse pancreas at early timepoints post-dosing, with pPERK returning to basal levels by 12 hours (30 mg/kg single oral dose).
Maintained near-complete pPERK inhibition (>80% inhibition) in mouse pancreas for the first 12 hours post-dosing (100 mg/kg single oral dose).
Induced 90% pPERK inhibition in 786-O tumors at 1 hour, which returned to baseline by 8 hours (30 mg/kg single oral dose).
Animal Model: BALB/c nude (6- to 8-week-old female; subcutaneously injected with 5×106 786-O RCC cells)[1]
Dosage: 3 mg/kg; 10 mg/kg; 30 mg/kg
Administration: p.o.; twice-a-day; 28 days
Result: Induced the greatest single-agent antitumor effect, resulting in 48% tumor growth inhibition (TGI) (30 mg/kg twice-a-day).
Animal Model: BALB/c nude (6- to 8-week-old female; subcutaneously injected with 5×106 786-O RCC cells)[1]
Dosage: 30 mg/kg
Administration: p.o.; twice-a-day; 28 days
Result: Inhibited VEGFR-TKI-induced pPERK accumulation in 786-O tumors.
Resulted in tumor regression relative to baseline when combined with axitinib or cabozantinib.
Enhanced the level of TGI beyond that of either monotherapy when combined with lenvatinib or sunitinib.
Induced a dose-dependent accumulation of ATF4 downstream targets (ASNS, CBS, CTH) in 786-O tumors treated with sunitinib.
Animal Model: NMRI nu/nu (Crl:NMRI-Foxn1nu; 4- to 6-week-old female; subcutaneously implanted with fragments from 18 RCC patient-derived xenograft (PDX) tumors)[1]
Dosage: 30 mg/kg
Administration: p.o.; twice-a-day; 28 days
Result: Resulted in 9 out of 18 PDX models achieving ≥50% tumor regression from baseline (partial responses) when combined with axitinib, compared with 2 out of 18 partial responses with axitinib monotherapy.
Led to 3 of 6 VHL-wildtype PDX models showing improved response to the combination treatment over axitinib monotherapy, with 2 achieving partial responses, 1 achieving 53% regression (partial response), 2 having stable disease, and 2 having progressive disease (with greater response to combination than monotherapies).
Animal Model: BALB/c nude (6- to 8-week-old female; subcutaneously injected with 5×106 786-O RCC cells, 5×106 A-498 RCC cells, or 6×106 Caki-1 RCC cells); NOD.SCID (6- to 8-week-old female; subcutaneously injected with 5×106 786-O RCC cells, 5×106 A-498 RCC cells, or 6×106 Caki-1 RCC cells)[1]
Dosage: 30 mg/kg
Administration: p.o.; twice-a-day; 28 days
Result: Resulted in 82% TGI in 786-O xenografts when combined with DC-101, improving the effects of each monotherapy.
Resulted in 78% TGI in A-498 xenografts when combined with DC-101, improving the effects of each monotherapy.
Induced only 24% TGI in Caki-1 xenografts when combined with DC-101, with no significant combination benefit observed.
Animal Model: BALB/c nude (6- to 8-week-old female; subcutaneously injected with 5×106 786-O RCC cells; tumors progressed on axitinib monotherapy for 14 days)[1]
Dosage: 30 mg/kg
Administration: p.o.; twice-a-day; 28 days
Result: Inhibited tumor growth by 47% relative to vehicle as single-agent.
Resulted in an average 20% tumor regression relative to baseline when combined with axitinib.
Reduced the proportion of Meca32+ endothelial cells, CD31+SMA+ mature blood vessels, and NG2+/MCAM+ pericytes in tumor sections beyond the effects of axitinib monotherapy when combined with axitinib.
Molecular Weight

512.51

Formula

C24H24F2N4O3.1/2C4H4O4
CAS No.
Appearance

Solid

Color

White to off-white

SMILES

CC(C)NC(C1=CC(C2=CC=C(C=C2C)NC([C@@H](C3=CC(F)=CC(F)=C3)O)=O)=CN=C1N)=O.O=C(O)/C=C/C(O)=O.[1/2]
Shipping

Room temperature in continental US; may vary elsewhere.
Storage

4°C, sealed storage, away from moisture and light

*In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture and light)

Solvent & Solubility
In Vitro: 

DMSO : 100 mg/mL (195.12 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 1.9512 mL 9.7559 mL 19.5118 mL
5 mM 0.3902 mL 1.9512 mL 3.9024 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 (sealed storage, away from moisture and light). 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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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    90% (20% SBE-β-CD in Saline)

    Solubility: ≥ 5 mg/mL (9.76 mM); Clear solution

    This protocol yields a clear solution of ≥ 5 mg/mL (saturation unknown).

    Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (50.0 mg/mL) to 900 μL 20% SBE-β-CD in Saline, and mix evenly.

    Preparation of 20% SBE-β-CD in Saline (4°C, storage for one week): 2 g SBE-β-CD powder is dissolved in 10 mL Saline, completely dissolve until clear.
  • Protocol 2

    Add each solvent one by one:  10% DMSO    90% Corn Oil

    Solubility: ≥ 5 mg/mL (9.76 mM); Clear solution

    This protocol yields a clear solution of ≥ 5 mg/mL (saturation unknown). If the continuous dosing period exceeds half a month, please choose this protocol carefully.

    Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (50.0 mg/mL) to 900 μL Corn oil, and mix evenly.

In Vivo Dissolution Calculator
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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).

*In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture and light)

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 (sealed storage, away from moisture and light). 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 1.9512 mL 9.7559 mL 19.5118 mL 48.7795 mL
5 mM 0.3902 mL 1.9512 mL 3.9024 mL 9.7559 mL
10 mM 0.1951 mL 0.9756 mL 1.9512 mL 4.8780 mL
15 mM 0.1301 mL 0.6504 mL 1.3008 mL 3.2520 mL
20 mM 0.0976 mL 0.4878 mL 0.9756 mL 2.4390 mL
25 mM 0.0780 mL 0.3902 mL 0.7805 mL 1.9512 mL
30 mM 0.0650 mL 0.3252 mL 0.6504 mL 1.6260 mL
40 mM 0.0488 mL 0.2439 mL 0.4878 mL 1.2195 mL
50 mM 0.0390 mL 0.1951 mL 0.3902 mL 0.9756 mL
60 mM 0.0325 mL 0.1626 mL 0.3252 mL 0.8130 mL
80 mM 0.0244 mL 0.1219 mL 0.2439 mL 0.6097 mL
100 mM 0.0195 mL 0.0976 mL 0.1951 mL 0.4878 mL
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    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:

HC-5404-Fu3034479-99-4PERKProtein kinase R-like endoplasmic reticulum kinasePKR-like endoplasmic reticulum kinase786-O tumorsVEGFR-TKIrenal cell carcinoma patient-derived xenograft modelsA-498 modelsCapan-2 pancreatic cancer xenograftsCaki-1 modelsHEK-293 cellsISR kinasesrenal cell carcinomaInhibitorinhibitorinhibit

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