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| Targets |
δPKC
Delcasertib targets the delta isoform of protein kinase C (PKC), specifically deltaPKC. It is a selective deltaPKC inhibitor. The cargo peptide is derived from the deltaV1-1 domain of deltaPKC, which binds to the activated form of the enzyme and prevents its translocation to the membrane and mitochondria, thereby inhibiting its pro-apoptotic and pro-inflammatory signaling. The TAT sequence enables the peptide to cross cell membranes, targeting ischemic cells where the disulfide bond is reduced, releasing the active inhibitor. This mechanism reduces injury associated with ischemia-reperfusion in acute myocardial infarction. |
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| ln Vitro |
Delcasertib hydrochloride (KAI-9803) is made up of an 11-amino acid (arginine-rich) cell-penetrating peptide and a specific delta-protein kinase C (δPKC) inhibitory peptide that is generated from the deltaV1-1 part of deltaPKC. Reversibly bonded disulfide links make up the acidic HIV type 1 transactivator sequence [1].
In vitro assays have confirmed that Delcasertib (KAI-9803) is a specific inhibitor of deltaPKC. The compound is composed of an 11-amino acid arginine-rich cell-penetrating peptide (TAT47-57) and a specific deltaPKC inhibitory peptide derived from the deltaV1-1 portion of deltaPKC, reversibly linked via a disulfide bond. This structure allows the inhibitor to be specifically delivered to cells, where it blocks the translocation and activation of deltaPKC. In various cell-based models of ischemia-reperfusion injury, treatment with Delcasertib reduces markers of apoptosis and oxidative stress. |
| ln Vivo |
Mice's liver, kidney, lung, heart, and brain exhibit specific inhibition of PKC translocation when administered intraperitoneally with delcasertib hydrochloride (KAI-9803) [1]. When given after the conclusion of ischemia, KAI-9803) was shown to lessen ischemia-reperfusion-induced heart damage in a rat model of acute myocardial infarction [1]. Patients having angioplasty following an acute myocardial infarction have been examined for the prevention of reperfusion injury with delcasertib hydrochloride (KAI-9803) [2].
In vivo, Delcasertib hydrochloride has been shown to improve ischemia-reperfusion injury in animal models of acute myocardial infarction (MI). When given after the conclusion of ischemia, it lessens ischemia-reperfusion-induced heart damage in rat models of acute MI. Intraperitoneal (i.p.) administration in mice results in selective inhibition of PKC translocation in tissues including the liver, kidney, lung, heart, and brain. The compound has been examined in patients undergoing angioplasty following an acute myocardial infarction for the prevention of reperfusion injury. These preclinical data indicate that Delcasertib limits infarct size and preserves cardiac function. |
| Enzyme Assay |
The in vitro binding and specificity of Delcasertib for deltaPKC are evaluated using peptide-based binding displacement assays or competition assays using isolated PKC isozymes (alpha, betaI, betaII, delta, ε, gamma, zeta, η, θ). Recombinant human PKC isozymes are incubated in assay buffer (20 mM HEPES, pH 7.5, 10 mM MgCl2, 0.5 mM CaCl2, 1 mM DTT, 0.1% Triton X-100) containing 100 microM ATP and 50-100 microg/mL phosphotidylserine as an activator. The inhibitor peptide (KAI-9803) is added at concentrations from 0.1 nM to 10 microM. The reaction is initiated by adding a PKC-specific substrate peptide (e.g., myelin basic protein, MBP). After 30 min at 30degC, the reaction is stopped with phosphoric acid. An aliquot is spotted onto P81 filter paper, washed, and incorporated radioactivity (33P-ATP) is counted. IC50 values are calculated. The disulfide-bonded peptide conjugate (Delcasertib) is also tested for stability in plasma, with cleavage assessed by HPLC-MS/MS to ensure release of the active cargo under reducing conditions.
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| Cell Assay |
Cellular internalization and functional inhibition of deltaPKC are assessed in cultured cardiomyocytes (e.g., H9c2 cells, neonatal rat ventricular myocytes, NRVMs) or other cell types relevant to ischemia (e.g., SH-SY5Y neurons). Cells are exposed to hypoxia/reoxygenation (H/R) or hydrogen peroxide (H2O2) to simulate oxidative stress and ischemia-reperfusion injury. Delcasertib hydrochloride (0.1-10 microM) is added to the culture medium either before the insult (pre-treatment) or at the start of reoxygenation. After 4-6 h of reoxygenation, deltaPKC translocation from the cytosol to membrane fractions and mitochondria is assessed by Western blot analysis of subcellular fractions. Apoptosis is measured by caspase-3/7 activity assay, Annexin V-FITC staining with flow cytometry, or by TUNEL assay. Cell viability is measured using MTT or LDH release assays. Mitochondrial membrane potential is measured using JC-1 dye. Delcasertib (3 microM) significantly blocks deltaPKC translocation and reduces apoptosis by 50-70% compared to H/R controls.
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| Animal Protocol |
Animal/Disease Models: Sixweeks old male Crl:CD(SD) rats[1]
Doses: 1 mg/kg (pharmacokinetic/PK Analysis). Route of Administration: Via the femoral vein. Experimental Results: The distribution to tissues such as the liver, kidney, and heart is facilitated by the reversible conjugation to TAT47-57. For in vivo efficacy, a rat model of acute myocardial ischemia-reperfusion (I/R) injury is commonly used. Adult male Sprague-Dawley rats (250-300 g) are anesthetized with pentobarbital (50 mg/kg, i.p.) and mechanically ventilated. A left thoracotomy is performed to expose the heart, and a suture is placed around the left anterior descending (LAD) coronary artery. Ischemia is induced for 30 minutes by tightening the suture (occlusion). Delcasertib hydrochloride (0.1-1 mg/kg) is dissolved in sterile PBS or saline and administered as an intravenous bolus injection via the femoral vein 5 minutes before reperfusion. The suture is then released for 2-24 hours of reperfusion. At the end of reperfusion, the LAD is re-occluded, and Evans blue dye is injected to delineate the area at risk (AAR). The heart is excised, sectioned, and stained with triphenyltetrazolium chloride (TTC) to distinguish infarcted tissue (pale, unstained) from viable myocardium. Infarct size is expressed as a percentage of the area at risk (IS/AAR). In vehicle-treated controls, IS/AAR is typically 40-60%. Delcasertib treatment (1 mg/kg) reduces IS/AAR to 20-30%, representing significant cardioprotection (p < 0.01). |
| ADME/Pharmacokinetics |
Pharmacokinetic studies in rodents show that Delcasertib hydrochloride is rapidly distributed to tissues including the liver, kidney, and heart. The reversible conjugation to TAT47-57 facilitates biodistribution. After intravenous administration of 1 mg/kg in rats, plasma half-life is ~10-15 minutes. The disulfide bond is cleaved in the reducing environment of cells, releasing the active cargo peptide. The cargo peptide has a shorter half-life (t1/2 ~5-10 min) and is rapidly eliminated by renal filtration due to its small size (Mw ~2916 Da for the full conjugate). Peak plasma concentration (Cmax) of the intact conjugate is achieved at ~5 min post-dose. The compound is not orally bioavailable and must be administered intravenously or intraperitoneally. The TFA salt form is used for research; the hydrochloride salt provides improved stability and handling properties.
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| Toxicity/Toxicokinetics |
Delcasertib hydrochloride is a research compound and has not received regulatory approval for clinical use. Toxicology studies in animal models (rats, dogs) indicate that at therapeutic doses (0.3-1 mg/kg, i.v.), the compound is well tolerated. No significant hemodynamic changes, hepatotoxicity (elevated ALT/AST), or nephrotoxicity (elevated BUN/creatinine) are observed. At supratherapeutic doses (≥10 mg/kg), transient hypotension and mild bradycardia may occur. The disulfide-linked TAT peptide conjugate shows low immunogenicity in acute dosing (single dose) but chronic toxicity studies have not been extensively published. The compound is not considered genotoxic (Ames test negative). Standard laboratory safety precautions (gloves, lab coat, goggles) should be used when handling the powder. Avoid inhalation of aerosols. Delcasertib hydrochloride is for research use only, not for human use.
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| References |
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| Additional Infomation |
Delcasertib is also known as KAI-9803 and BMS-875944. The deltaPKC isozyme is a key mediator of reperfusion injury; its activation in the early minutes of reperfusion triggers a cascade leading to cell death via mitochondrial dysfunction and opening of the mitochondrial permeability transition pore (mPTP). By specifically inhibiting deltaPKC, Delcasertib interrupts this signaling pathway, reducing myocyte death and preserving cardiac function. This compound represents a molecularly targeted approach to limit myocardial infarct size, a concept known as “ischemic preconditioning pharmacology.” The free base (non-salt) form of the compound is prone to instability; the hydrochloride salt retains the same biological activity. Delcasertib has been investigated in Phase II clinical trials for the treatment of acute myocardial infarction (MI) and for the prevention of reperfusion injury in patients undergoing primary percutaneous coronary intervention (PCI). However, development was not continued to Phase III. Despite this, it remains a valuable research tool compound for understanding the role of deltaPKC in ischemia-reperfusion injury. The TAT carrier peptide technology has been widely adopted for intracellular delivery of impermeable molecules. The compound is strictly for research purposes.
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| Molecular Formula |
C120H200CLN45O34S2
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| Molecular Weight |
2916.74
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| Related CAS # |
Delcasertib;949100-39-4
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| Appearance |
Typically exists as solid at room temperature
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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) |
H2O :~100 mg/mL (~34.28 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 50 mg/mL (17.14 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
(Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.3428 mL | 1.7142 mL | 3.4285 mL | |
| 5 mM | 0.0686 mL | 0.3428 mL | 0.6857 mL | |
| 10 mM | 0.0343 mL | 0.1714 mL | 0.3428 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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