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| Targets |
ZYF-0033 targets hematopoietic progenitor kinase 1 (HPK1 or MAP4K1), a serine/threonine protein kinase that acts as a critical negative regulator of immune cell function. By inhibiting HPK1, ZYF-0033 blocks immunosuppressive HPK1 signaling, which in turn potentiates T-cell activation. This leads to enhanced anticancer immune responses and reduced tumor growth.
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| ln Vitro |
ZYF-0033 is a highly potent HPK1 inhibitor (IC50 < 10 nM). In vitro, it decreases the phosphorylation of SLP76 (at serine 376), a downstream target of HPK1. At a concentration of 100 nM, it increases the proliferation of CD4+ and CD8+ T cells and enhances the secretion of IFN-γ. This promotes anticancer immune responses by blocking the immunosuppressive function of HPK1.
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| ln Vivo |
In vivo, ZYF-0033 (also known as HPK1-IN-22) promotes anticancer immune responses and inhibits tumor growth. In the 4T-1 syngeneic mouse model, it increases the intratumoral infiltration of DCs, NK cells, and CD107a+CD8+ T cells. Simultaneously, it decreases the infiltration of immunosuppressive regulatory T cells, as well as PD-1+, TIM-3+, and LAG3+ CD8+ T cells.
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| Enzyme Assay |
The in vitro biochemical activity of ZYF-0033 is measured by its ability to inhibit HPK1 kinase activity. This is typically assessed by measuring the phosphorylation of a substrate, such as MBP protein, in the presence of varying concentrations of the compound. The IC50, which is less than 10 nM, is determined from the inhibition curve. The compound is dissolved in DMSO and diluted in the appropriate kinase assay buffer.
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| Cell Assay |
In vitro cellular assays involve treating immune cells, such as T cells, with ZYF-0033. The inhibition of HPK1 is confirmed by measuring the reduction in phosphorylation of its downstream substrate, SLP76 (at serine 376). The compound's effect on T-cell function is then assessed by measuring proliferation, as well as the production of cytokines like IFN-γ.
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| Animal Protocol |
In vivo studies for ZYF-0033 are typically conducted in syngeneic mouse tumor models, such as the 4T-1 model. The compound is administered orally, and its effects on tumor growth and the tumor immune microenvironment are evaluated. This includes analysis of immune cell infiltration (e.g., DCs, NK cells, CD8+ T cells, and regulatory T cells) by flow cytometry, as well as assessment of T-cell function.
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| ADME/Pharmacokinetics |
ZYF-0033 has a molecular weight of 462.61 g/mol and the formula C26H30N4O2S. It is an orally effective small molecule, typically appearing as a white to off-white solid powder. It is soluble in DMSO (80 mg/mL). The recommended storage for the powder is -20°C for up to 3 years and in solvent at -80°C for up to 6 months. Its LogP is 3.4.
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| Toxicity/Toxicokinetics |
As a research compound, the full toxicity profile of ZYF-0033 is still under investigation. However, its mechanism of action as an immune modulator suggests potential for immune-related adverse events, similar to other immunotherapies. Standard preclinical safety studies, including acute and repeated-dose toxicity assessments in animal models, would be necessary to fully characterize its safety profile for any potential therapeutic use.
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| References | |
| Additional Infomation |
ZYF-0033 (CAS 2380300-79-6) is an orally effective, small-molecule HPK1 inhibitor with an IC50 of <10 nM. It is also known as Fimsosertib, HPK1-IN-22, and ZYF0033. By inhibiting HPK1, it promotes anticancer immune responses. Its potential in cancer immunotherapy is being actively researched. This product is for research use only and is not for human therapeutic applications.
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| Molecular Formula |
C26H30N4O2S
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| Molecular Weight |
462.607004642487
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| Exact Mass |
462.208
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| CAS # |
2380300-79-6
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| PubChem CID |
155905549
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| Appearance |
White to off-white solid powder
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| LogP |
3.4
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
33
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| Complexity |
699
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC(C)(O)C#CC1=CC=CC(COC2=CC(C3SC(C4CCN(C)CC4)=NC=3)=CN=C2N)=C1
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| InChi Key |
BJNWUKRWOQERPQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C26H30N4O2S/c1-26(2,31)10-7-18-5-4-6-19(13-18)17-32-22-14-21(15-28-24(22)27)23-16-29-25(33-23)20-8-11-30(3)12-9-20/h4-6,13-16,20,31H,8-9,11-12,17H2,1-3H3,(H2,27,28)
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| Chemical Name |
4-[3-[[2-amino-5-[2-(1-methylpiperidin-4-yl)-1,3-thiazol-5-yl]pyridin-3-yl]oxymethyl]phenyl]-2-methylbut-3-yn-2-ol
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| Synonyms |
Fimsosertib; ZYF-0033; ZYF0033; 2380300-79-6; 4-{3-[({2-Amino-5-[2-(1-methylpiperidin-4-yl)-1,3-thiazol-5-yl]pyridin-3-yl}oxy)methyl]phenyl}-2-methylbut-3-yn-2-ol; 4-(3-(((2-amino-5-(2-(1-methylpiperidin-4-yl)-1,3-thiazol-5-yl)pyridin-3-yl)oxy)methyl)phenyl)-2-methylbut-3-yn-2-ol; RefChem:512920; 893-752-1;
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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 (216.2 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1616 mL | 10.8082 mL | 21.6165 mL | |
| 5 mM | 0.4323 mL | 2.1616 mL | 4.3233 mL | |
| 10 mM | 0.2162 mL | 1.0808 mL | 2.1616 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.
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