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| Targets |
HPK1
HPK1 (hematopoietic progenitor kinase 1, MAP4K1). HPK1-IN-32 is a potent and selective inhibitor of HPK1, a serine/threonine kinase that functions as a negative regulator of T-cell receptor (TCR) signaling. HPK1 phosphorylates and activates downstream targets that limit T-cell activation, including SLP-76. By inhibiting HPK1, the compound enhances TCR signaling and promotes T-cell activation, proliferation, and cytokine production. |
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| ln Vitro |
With an IC50 of 65 nM, HPK1-IN-32 (Example A34, 0-2 μM, 2 h) suppresses pSLP76 activity in Jurkat cells[1].
HPK1-IN-32 is a potent and selective HPK1 inhibitor that enhances T-cell activation by blocking the negative regulatory function of HPK1. By inhibiting HPK1-mediated phosphorylation of SLP-76 and other substrates, the compound enhances TCR signaling, leading to increased T-cell proliferation, cytokine production (IL-2, IFN-γ), and anti-tumor activity. Its selectivity for HPK1 over other kinases is a key feature of its pharmacological profile. |
| ln Vivo |
In vivo, HPK1-IN-32 enhances T-cell-mediated anti-tumor immune responses by inhibiting HPK1 and relieving the negative regulation of TCR signaling. By promoting T-cell activation and proliferation, the compound has potential for cancer immunotherapy. Its efficacy would be assessed in syngeneic mouse tumor models by measuring tumor growth inhibition, T-cell infiltration, and survival.
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| Enzyme Assay |
In vitro enzyme activity assays for HPK1-IN-32 are performed using recombinant HPK1 kinase. The enzyme is incubated with its substrate (e.g., a peptide derived from SLP-76) in the presence of ATP and increasing concentrations of the compound. Kinase activity is measured by detecting phosphorylation of the substrate, and the IC50 is determined from the dose-response curve.
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| Cell Assay |
Cellular assays for HPK1-IN-32 involve treating T cells with the compound and measuring enhancement of TCR signaling. T cells are stimulated with anti-CD3/CD28 antibodies in the presence of increasing concentrations of the compound. Readouts include IL-2 production (measured by ELISA), T-cell proliferation (measured by CFSE dilution or thymidine incorporation), and phosphorylation of downstream signaling proteins (e.g., ERK, PLC-γ1).
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| Animal Protocol |
In vivo efficacy of HPK1-IN-32 would be evaluated in syngeneic mouse tumor models. The compound could be administered orally or via injection, and its effects on tumor growth, T-cell infiltration, and survival would be assessed. Efficacy endpoints would include tumor volume, tumor-infiltrating lymphocyte analysis, and systemic cytokine levels. The compound's ability to enhance anti-tumor immune responses would be evaluated.
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| ADME/Pharmacokinetics |
HPK1-IN-32 has a molecular formula of C22H21ClN6O3 and a molecular weight of 452.89. It is a small-molecule HPK1 inhibitor with potential for oral bioavailability. As a research compound, its pharmacokinetic properties would be characterized by standard ADME studies. The compound should be stored under recommended conditions. It is for research use only and is not intended for human therapeutic use.
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| Toxicity/Toxicokinetics |
No specific toxicity data is available for HPK1-IN-32. As an HPK1 inhibitor that enhances T-cell activation, its safety profile would be an important consideration for therapeutic applications. Potential toxicities could include immune-related adverse events similar to other immunomodulatory agents. Standard preclinical safety studies would be required to evaluate its safety for potential therapeutic applications.
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| References | |
| Additional Infomation |
HPK1-IN-32 (CAS#: 2766481-17-6) is a potent and selective inhibitor of hematopoietic progenitor kinase 1 (HPK1, MAP4K1). It has a molecular formula of C22H21ClN6O3 and a molecular weight of 452.89. By inhibiting HPK1, the compound enhances T-cell activation and has potential applications in cancer immunotherapy. It is a research tool and is not approved for clinical use.
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| Molecular Formula |
C28H37FN8O2
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| Molecular Weight |
536.64
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| Exact Mass |
536.302
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| CAS # |
2766481-17-6
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| PubChem CID |
164889473
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| Appearance |
White to off-white solid powder
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| LogP |
2.4
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
39
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| Complexity |
790
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1CN(C)CCC1N1C=C(OC2N=C(C3=CC(C)=C(C(NCCN4CC[C@@H](F)C4)=O)C(C)=C3)C=NC=2N)C=N1
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| InChi Key |
IGTYEXMPMYGLTR-OAQYLSRUSA-N
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| InChi Code |
InChI=1S/C28H37FN8O2/c1-18-12-20(13-19(2)25(18)27(38)31-7-11-36-10-4-21(29)16-36)24-15-32-26(30)28(34-24)39-23-14-33-37(17-23)22-5-8-35(3)9-6-22/h12-15,17,21-22H,4-11,16H2,1-3H3,(H2,30,32)(H,31,38)/t21-/m1/s1
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| Chemical Name |
4-[5-amino-6-[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]oxypyrazin-2-yl]-N-[2-[(3R)-3-fluoropyrrolidin-1-yl]ethyl]-2,6-dimethylbenzamide
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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: 50 mg/mL (93.17 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.66 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.66 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8634 mL | 9.3172 mL | 18.6345 mL | |
| 5 mM | 0.3727 mL | 1.8634 mL | 3.7269 mL | |
| 10 mM | 0.1863 mL | 0.9317 mL | 1.8634 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.
Link: https://clinicaltrials.gov/ct2/show/NCT04164199
Conditions:Advanced MalignanciesLink: https://clinicaltrials.gov/ct2/show/NCT05635708
Conditions:Non-small Cell Lung Cancer|Metastatic Non-small Cell Lung CancerLink: https://clinicaltrials.gov/ct2/show/NCT04649385
Conditions:Advanced Solid Tumor
Title:A Study of Gimistotug (BGB-A445) in Combination With Other Investigational Agents in Participants With Non-Small Cell Lung Cancer
Status:Completed
updateDate:2026-01-05
Ctid:NCT06029127
Link: https://clinicaltrials.gov/ct2/show/NCT06029127
Conditions:Non-Small Cell Lung CancerProducts are for research use only; We do not sell to patients
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