Delcasertib (KAI-9803)
(Synonyms: BMS-875944) 目录号 : GC32466
Delcasertib (KAI-9803) (KAI-9803) 是一种有效的选择性 δ-蛋白激酶 C (δPKC) 抑制剂。
Cas No.:949100-39-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
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Animal experiment: |
Rats[1]For pharmacokinetic studies, 14Delcasertib (KAI-9803) (1 mg/kg) is administered to Six-week-old male Crl:CD(SD) rats via the femoral vein and approximately 0.2 mL of blood is collected from the jugular vein at 1, 2, 5, 10, and 15 min postdose with a heparinized syringe containing 10 μL of 400 mM diisopropylfluorophosphate dissolved in acetonitrile to prevent rapid degradation of the peptide. The radioactivity in the blood and plasma samples is measured using a liquid scintillation counter[1]. |
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References: [1]. Miyaji Y, et al. Distribution of KAI-9803, a novel δ-protein kinase C inhibitor, after intravenous administration to rats. Drug Metab Dispos. 2011 Oct;39(10):1946-53. |
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Delcasertib (KAI-9803) is a potent and selective δ-protein kinase C (δPKC) inhibitor.
Delcasertib (KAI-9803) is composed of a selective δ-protein kinase C (δPKC) inhibitor peptide derived from the δV1-1 portion of δPKC (termed "cargo peptide"), conjugated reversibly to the cell-penetrating peptide 11-amino acid, arginine-rich sequence of the HIV type 1 transactivator protein (TAT47-57; termed "carrier peptide") via a disulfide bond[1].
Delcasertib (KAI-9803) administration at the end of ischemia has been found to reduce cardiac damage caused by ischemia-reperfusion in a rat model of acute myocardial infarction. 14C-KAI-9803 is rapidly delivered to many tissues, including the heart (1.21 μg eq/g tissue), while being quickly cleared from the systemic circulation. The distribution of Delcasertib (KAI-9803) to tissues such as the liver, kidney, and heart is facilitated by the reversible conjugation to TAT47-57[1]. KAI-9803 ameliorates pathological conditions in acute myocardial infarction and reduce pain via specific modulation of membrane-translocation of PKC delta or epsilon. Delcasertib (KAI-9803) has an acceptable safety and tolerability profile when delivered via intracoronary injection during primary percutaneous coronary intervention for ST-segment elevation myocardial infarction[2].
References:
[1]. Miyaji Y, et al. Distribution of KAI-9803, a novel δ-protein kinase C inhibitor, after intravenous administration to rats. Drug Metab Dispos. 2011 Oct;39(10):1946-53.
[2]. Bates E, et al. Intracoronary KAI-9803 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction. Circulation. 2008 Feb 19;117(7):886-96.
| Cas No. | 949100-39-4 | SDF | |
| 别名 | BMS-875944 | ||
| 分子式 | C180H199N45O34S2 | 分子量 | 2880.28 |
| 溶解度 | DMSO : ≥ 100 mg/mL (34.72 mM) | 储存条件 | Store at -20° C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 0.3472 mL | 1.7359 mL | 3.4719 mL |
| 5 mM | 0.0694 mL | 0.3472 mL | 0.6944 mL |
| 10 mM | 0.0347 mL | 0.1736 mL | 0.3472 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Intracoronary KAI-9803 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction
Circulation 2008 Feb 19;117(7):886-96.PMID:18250271DOI:10.1161/CIRCULATIONAHA.107.759167.
Background: KAI-9803, a delta-protein kinase C inhibitor, has been shown to ameliorate injury associated with ischemia and reperfusion in animal models of acute myocardial infarction (MI). Methods and results: Direct Inhibition of delta-Protein Kinase C Enzyme to Limit Total Infarct Size in Acute Myocardial Infarction (DELTA MI) was a "first-in-human," dose-escalation study that evaluated the safety, tolerability, and activity of KAI-9803 for patients with acute anterior ST-segment elevation MI undergoing primary percutaneous coronary intervention. Patients who presented within 6 hours of symptom onset and had an occluded left anterior descending infarct artery on angiography were randomized in a 2:1 fashion to receive 1 of 4 doses of KAI-9803 (cohort 1, 0.05 mg; cohort 2, 0.5 mg; cohort 3, 1.25 mg; cohort 4, 5.0 mg) versus blinded concurrent placebo delivered in 2 divided doses via intracoronary injection before and after reestablishment of antegrade epicardial flow with percutaneous coronary intervention. Safety and biomarker end points were assessed. Overall, 154 patients were randomized and treated with study drug (37 in cohort 1, 38 in cohort 2, 38 in cohort 3, 41 in cohort 4). The incidence of serious adverse events was similar between patients treated with KAI-9803 versus placebo. Other safety end points, including changes in QT intervals and standard laboratory values after study drug administration, were similar between treatment groups. Although the study was not powered to demonstrate efficacy with the biomarker end points assessed, signs of drug activity with KAI-9803 were suggested by trends for consistent, nonsignificant reductions in creatine kinase-MB area under the curve and ST-recovery area under the curve values across all dosing cohorts with KAI-9803 compared with concurrent placebo, and similar trends were demonstrated for improvements in (99m)technetium sestamibi infarct size values with active study drug in cohorts 1, 2, and 3. Conclusions: KAI-9803 had an acceptable safety and tolerability profile when delivered via intracoronary injection during primary percutaneous coronary intervention for ST-segment elevation MI. Signs of potential drug activity were demonstrated with biomarker end points in this small exploratory study, indicating that further testing of KAI-9803 as an adjunctive therapy for ST-segment elevation MI is warranted.
Distribution of KAI-9803, a novel 未-protein kinase C inhibitor, after intravenous administration to rats
Drug Metab Dispos 2011 Oct;39(10):1946-53.PMID:21712433DOI:10.1124/dmd.111.040725.
KAI-9803 is composed of a selective 未-protein kinase C (未PKC) inhibitor peptide derived from the 未V1-1 portion of 未PKC (termed "cargo peptide"), conjugated reversibly to the cell-penetrating peptide 11-amino acid, arginine-rich sequence of the HIV type 1 transactivator protein (TAT鈧勨倗鈧嬧倕鈧? termed "carrier peptide") via a disulfide bond. KAI-9803 administration at the end of ischemia has been found to reduce cardiac damage caused by ischemia-reperfusion in a rat model of acute myocardial infarction. In the study presented here, we examined the TAT鈧勨倗鈧嬧倕鈧?mediated distribution of KAI-9803 in rats after a single intravenous bolus administration (1 mg/kg). 鹿鈦碈-KAI-9803 was rapidly delivered to many tissues, including the heart (1.21 渭g eq/g tissue), while being quickly cleared from the systemic circulation. The microautoradiography analysis showed that 鹿鈦碈-KAI-9803 was effectively delivered into various cells, including cardiac myocytes and cardiac endothelial cells within 1 min after dosing. The tissue distribution of 鹿虏鈦礗-labeled KAI-9803 was compared to that of 鹿虏鈦礗-labeled cargo peptide; this comparison demonstrated that the distribution of KAI-9803 to tissues such as the liver, kidney, and heart was facilitated by the reversible conjugation to TAT鈧勨倗鈧嬧倕鈧? In an in vitro cardiomyocyte study, the extent of 鹿虏鈦礗-KAI-9803 internalization was greater at 37掳C than that at 4掳C, whereas the internalization of the 鹿虏鈦礗-cargo peptide at 37掳C was not observed, indicating that the uptake of 鹿虏鈦礗-KAI-9803 into the cardiomyocytes was mediated by the TAT鈧勨倗鈧嬧倕鈧?carrier. Our studies demonstrated that after a single intravenous administration, KAI-9803 can be delivered into the target cells in the liver, kidney, and heart by a TAT鈧勨倗鈧嬧倕鈧?mediated mechanism.
Gateways to clinical trials
Methods Find Exp Clin Pharmacol 2007 Jul-Aug;29(6):427-37.PMID:17922073doi
[111In]-DOTA-cG250, [131I]-Metuximab injection, [177Lu]-DOTA-cG250; Anatumomab mafenatox, AP-12009; BIBW-2992, Biricodar dicitrate; Cediranib, Cilengitide, Clevidipine, CNTO-528, CNTO-95, CP-870893; Disufenton sodium, DNK-333A; Ecallantide, Enzastaurin hydrochloride, Etravirine, Exatecan mesilate; Fingolimod hydrochloride; Human insulin, Hyaluronic acid; Indisulam, Inhaled insulin, Insulin glargine, Ipilimumab, Irofulven, Ispronicline, ITF-282; J591; KAI-9803; L-Arginine hydrochloride, Laropiprant, LY-518674; Matuzumab, MB-7133, Methylnaltrexone bromide, MVA-5T4; Nemifitide ditriflutate; Obatoclax mesylate, Oral insulin; P-276-00, PF-562271, Picolinic acid; Quercetin; R-109339, R-547, Rivaroxaban, Ruboxistaurin mesilate hydrate; Seliciclib; Terameprocol, Tilarginine hydrochloride, Tolvaptan, Uracil; Vincristine.
PKC delta and epsilon in drug targeting and therapeutics
Recent Pat DNA Gene Seq 2009;3(2):96-101.PMID:19519579DOI:10.2174/187221509788654205.
Protein kinase C (PKC) belongs to the serine and threonine kinase family. At least ten PKC isoforms have been identified and subdivided into three groups: classical (alpha, beta I, beta II and gamma), novel (delta, epsilon, theta and eta), and atypical (zeta and iota/lambda). Two calcium-insensitive isoforms of novel PKC, PKC delta and epsilon, have received particular attention as promising targets for new drugs. PKCs play a multifaceted role in cellular responses in a range of tissues. Professor Mochly-Rosen's group and KAI Pharmaceuticals Inc. have developed drugs targeted against PKC delta (KAI-9803) and epsilon (KAI-1678). These drugs ameliorate pathological conditions in acute myocardial infarction and reduce pain via specific modulation of membrane-translocation of PKC delta or epsilon. Another research group has recently used the KinAce() approach to produce PKC epsilon-abrogating peptides (KCe-12 and KCe-16) that are based on the catalytic domain of PKC. These peptides specifically inhibit PKC epsilon and ameliorate pathological conditions in a rodent insulin resistance model. This review describes the development of these therapeutic drugs targeting PKC delta and epsilon by two independent groups in the light of recent patents.
Inhibition of delta-protein kinase C by Delcasertib as an adjunct to primary percutaneous coronary intervention for acute anterior ST-segment elevation myocardial infarction: results of the PROTECTION AMI Randomized Controlled Trial
Eur Heart J 2014 Oct 1;35(37):2516-23.PMID:24796339DOI:10.1093/eurheartj/ehu177.
Aims: Delcasertib is a selective inhibitor of delta-protein kinase C (delta-PKC), which reduced infarct size during ischaemia/reperfusion in animal models and diminished myocardial necrosis and improved reperfusion in a pilot study during primary percutaneous coronary intervention (PCI) for ST elevation myocardial infarction (STEMI). Methods and results: A multicentre, double-blind trial was performed in patients presenting within 6 h and undergoing primary PCI for anterior (the primary analysis cohort, n = 1010 patients) or inferior (an exploratory cohort, capped at 166 patients) STEMI. Patients with anterior STEMI were randomized to placebo or one of three doses of Delcasertib (50, 150, or 450 mg/h) by intravenous infusion initiated before PCI and continued for 鈭?.5 h. There were no differences between treatment groups in the primary efficacy endpoint of infarct size measured by creatine kinase MB fraction area under the curve (AUC) (median 5156, 5043, 4419, and 5253 ng h/mL in the placebo, Delcasertib 50, 150, and 450 mg/mL groups, respectively) in the anterior STEMI cohort. No treatment-related differences were seen in secondary endpoints of infarct size, electrocardiographic ST-segment recovery AUC or time to stable ST recovery, or left ventricular ejection fraction at 3 months. No differences in rates of adjudicated clinical endpoints (death, heart failure, or serious ventricular arrhythmias) were observed. Conclusions: Selective inhibition of delta-PKC with intravenous infusion of Delcasertib during PCI for acute STEMI in a population of patients treated according to contemporary standard of care did not reduce biomarkers of myocardial injury.