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Purity: ≥98%
Samuraciclib HCl (ICEC-0942; PPDA001; CT-7001), the hydrochloride salt of Samuraciclib, is a novel, potent, orally bioavailable and selective CDK7 inhibitor with potential anticancer activity. Its IC50 values are 41 nM and 578 nM, respectively, for CDK2/cycE1 and CDK7/CycH/MAT1. Cancer treatment may be possible with it. IC50 values for CDK1, CDK2, CDK5, and CDK9 were 45-, 15-, 230-, and 30-fold higher than that of CDK7, which it selectively inhibits at a 40nM concentration. GI50 values range between 0.2 and 0.3 µM, indicating that a broad spectrum of cancer types are sensitive to CDK7 inhibition in vitro.
| Targets |
CDK7 (IC50 = 41 nM); CDK2 (IC50 = 578 nM); CDK1 (IC50 = 1.8 μM); CDK4 (IC50 = 49 μM); CDK5 (IC50 = 9.4 μM); CDK6 (IC50 = 41 nM); CDK7 (IC50 = 34 μM); CDK9 (IC50 = 1.2 μMM)
CDK7 (IC₅₀ = 40 nM) CDK1 (IC₅₀ = 1800 nM, 45-fold higher than CDK7) CDK2 (IC₅₀ = 600 nM, 15-fold higher) CDK5 (IC₅₀ = 9200 nM, 230-fold higher) CDK9 (IC₅₀ = 1200 nM, 30-fold higher) CDK4 and CDK6 were not substantially inhibited. ERK8, STK33, CHK2, CLK2, and PHK were inhibited at 10 µM ICEC0942, but to an extent similar to CDK2 inhibition.[1] |
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| ln Vitro |
ICEC0942 inhibits CDK7 in a wide range of cancer types, with GI50 values ranging from 0.2 to 0.3 µM. In the MCF7 breast cancer cell line, ICEC0942 dose- and time-dependently inhibits the phosphorylation of PolII, CDK1, CDK2, and RB (retinoblastoma). ICEC0942 stimulates apoptosis and cell cycle arrest by preventing CDK7 substrate phosphorylation[1].
ICEC0942 inhibits the growth of breast cancer cell lines (MCF7, T47D, MDA-MB-231, HS578T, MDA-MB-468) with GI₅₀ values between 0.18–0.33 µM.[1] The non-tumorigenic breast epithelial cell line MCF10A and primary human mammary epithelial cells (HMEC) were 2- and 3.8-times less sensitive, respectively, with GI₅₀ values of 0.67 µM and 1.25 µM.[1] In the NCI-60 panel screening, ICEC0942 inhibited all 60 cancer cell lines with a median GI₅₀ of 0.25 µM.[1] ICEC0942 inhibits phosphorylation of CDK7 substrates: PolII CTD at Ser2 and Ser5, CDK1 at Thr161, CDK2 at Thr160, and retinoblastoma (Rb) phosphorylation in HCT116 and MCF7 cells in a dose- and time-dependent manner.[1] It also inhibits ER phosphorylation at Ser118 in MCF7 cells.[1] Treatment with ICEC0942 induces caspase 3/7 activity and PARP cleavage, indicating apoptosis.[1] Cell cycle analysis shows accumulation of cells in G2/M phase in asynchronous HCT116 and MCF7 cells.[1] ICEC0942 blocks release from G1 and slows release from S-phase arrest in synchronized MCF7 cells.[1] Combination treatment with tamoxifen or fulvestrant enhances growth inhibition in MCF7 cells compared to single-agent treatment.[1] |
| ln Vivo |
ICEC0942 has strong anti-tumor effects in colorectal and breast cancer xenografts. Male CD1 mice are given 10 mg/kg ICEC0942 intravenously (IV), subcutaneously (SC), or orally (PO) for pharmacokinetic purposes. The biphasic decline in ICEC0942 levels in plasma suggests that the compound is rapidly distributed into tissues. Cl(plasma) is measured at 78 ml/min/kg in male CD1 mice after receiving ICEC0942 intraperitoneally at a dose of 10 mg/kg. Ratio of blood to plasma (Bl/Pl) is 1.81. ICEC0942 has a moderate half-life for this species, lasting 1.9 hours. One PO administration (100 mg/kg) of ICEC0942 results in only a small amount of metabolization—13.5%—after two and four hours. Comparing oral bioavailability (F%) at 30% with single PO and IV administration at 10 mg/kg for exposure (AUCt). The median Tmax for PO administration is two hours, and a higher dose has no effect. AUCt, or the total exposure over time, and Cmax have a linear relationship with dose within this dose range. Six hours after administration, there is a noticeable build-up of ICEC0942 in the tumors of tumor-bearing mice. Tumor ICEC0942 levels are not as high as plasma levels[1].
Oral administration of ICEC0942 at 100 mg/kg/day inhibits MCF7 breast cancer xenograft growth by 60% at day 14 (p = 0.0001), with reduced phosphorylation of PolII Ser2/Ser5, ER Ser118, CDK1, and CDK2 in tumors and PBMCs.[1] In HCT116 colon cancer xenografts, daily oral ICEC0942 (100 mg/kg) inhibits tumor growth by 60% at day 13 (p < 0.0001), with reduced PolII Ser2/Ser5 phosphorylation in tumors and PBMCs.[1] Combination therapy of ICEC0942 (50 mg/kg) with tamoxifen (100 µg/mouse) results in complete growth arrest of MCF7 xenografts.[1] |
| Enzyme Assay |
Kinase activities of purified CDK/cyclin complexes were assayed using peptide substrates. For CDK1/cyclin A1, CDK2/cyclin A1, CDK4/cyclin D1, CDK5/p35NCK, and CDK6/cyclin D1, the Rb-CTF peptide was used as substrate. For CDK7/cyclin H/MAT1 and CDK9/cyclin T1, a PolII CTD peptide (sequence: YSPTSPSYSPTSPSYSPTSPS) was used.[1]
Kinase inhibition was evaluated by measuring remaining ATP after the kinase reaction using a luciferase-based assay. Inhibition curves were generated by testing increasing concentrations of ICEC0942.[1] A 117-kinase panel screening was performed at 10 µM ICEC0942 to assess selectivity.[1] |
| Cell Assay |
Cell proliferation was assessed using the sulforhodamine B (SRB) assay. Cells were treated with increasing concentrations of ICEC0942 for 48 hours, fixed, stained with SRB, and absorbance measured to determine GI₅₀.[1]
For immunoblotting, cells were lysed in RIPA buffer with protease and phosphatase inhibitors. Proteins were separated by SDS-PAGE, transferred to membranes, and probed with specific antibodies.[1] Cell cycle analysis was performed by flow cytometry. Cells were treated with ICEC0942 for 24 hours, fixed, stained with propidium iodide, and analyzed using flow cytometry.[1] Apoptosis was assessed by Annexin V and propidium iodide staining followed by flow cytometry, and by Caspase-Glo 3/7 assay according to manufacturer's protocol.[1] For synchronization, cells were arrested in G0/G1 by serum starvation, in S-phase by double thymidine block, and in G2/M by thymidine-nocodazole block. After release, cells were treated with ICEC0942 and analyzed by flow cytometry.[1] |
| Animal Protocol |
seven-week old female nu/nu-BALB/c athymic nude mice with tumour xenograft
100 mg/kg/day PO Tumor xenografts were established by subcutaneous injection of 5×10⁶ MCF7 or HCT116 cells into the flanks of female nu/nu-BALB/c athymic nude mice. For MCF7 xenografts, a 0.72 mg 17β-estradiol 60-day release pellet was implanted subcutaneously 24 hours before cell inoculation.[1] When tumor volumes reached 100–200 mm³, mice were randomized and treated daily by oral gavage with ICEC0942 prepared in 10% DMSO/PBS (vehicle). Doses used were 50 mg/kg and 100 mg/kg.[1] Tamoxifen (100 µg/mouse) was administered orally alone or in combination with ICEC0942.[1] Tumor volumes were measured twice weekly, and animal weights were recorded daily.[1] At study endpoints, tumors were collected for protein lysate preparation or paraffin embedding, and blood was collected for analysis.[1] |
| ADME/Pharmacokinetics |
In male CD1 mice, the bioavailability (F%) of ICEC0942 at an oral dose of 10 mg/kg was 30%. [1]
Plasma clearance (Clₚₗₐₛₘₐ) was 78 mL/min/kg, and blood clearance (Clբₗₒₒ𝒹) was 43 mL/min/kg. [1] Volume of distribution (Vd) was 13.0 L/kg, indicating extensive tissue distribution. [1] Half-life (t₁/₂) was 1.9 hours. [1] Log D₇.₄ was 1.88, indicating good lipid solubility. [1] Plasma protein binding was 90.8% (free fraction = 9.2%). [1] Metabolite analysis showed that only 13.5% of ICEC0942 was metabolized to oxidation or dehydrogenation products 4 hours after a single oral dose (100 mg/kg). [1] Cmax and AUC increased linearly with dose within the tested dose range. [1] |
| Toxicity/Toxicokinetics |
In the HCT116 xenograft study, treatment with ICEC0942 (100 mg/kg/day) resulted in a decrease in blood lymphocyte count, but no significant weight loss or abnormal blood biochemistry was observed. [1]
In vitro assays did not detect hERG susceptibility. [1] |
| References | |
| Additional Infomation |
ICEC0942 is a non-covalent ATP-competitive CDK7 inhibitor and an oral bioavailability analog of BS-181 with superior drug-like properties. [1]
It inhibits transcription by blocking PolII CTD phosphorylation and regulates cell cycle progression by inhibiting the activation of CDK1 and CDK2. [1] This compound shows potential for treating ER-positive breast cancer, both as monotherapy and in combination with endocrine therapies such as tamoxifen. [1] It may also be effective against other transcription factor-dependent cancers, such as acute leukemia and small cell lung cancer. [1] The CDK7 complex (CDK7, cyclin H, MAT1) is overexpressed in breast tumors, especially in ER-positive, endocrine-resistant breast cancer, suggesting a therapeutic window for CDK7 inhibitors. [1] |
| Molecular Formula |
C22H31CLN6O
|
|---|---|
| Molecular Weight |
430.974143266678
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| Exact Mass |
430.22
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| Elemental Analysis |
C, 61.31; H, 7.25; Cl, 8.23; N, 19.50; O, 3.71
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| CAS # |
1805789-54-1
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| Related CAS # |
Samuraciclib hydrochloride hydrate;Samuraciclib hydrochloride hydrate;Samuraciclib;1805833-75-3
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| PubChem CID |
91844732
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| Appearance |
White to light yellow solid powder
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| Hydrogen Bond Donor Count |
5
|
| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
30
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| Complexity |
500
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| Defined Atom Stereocenter Count |
2
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| SMILES |
CC(C)C1=C2N=C(C=C(N2N=C1)NCC3=CC=CC=C3)NC[C@H]4CCNC[C@@H]4O.Cl
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| InChi Key |
YMNPLAHCOLEZJE-ZFNKBKEPSA-N
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| InChi Code |
InChI=1S/C22H30N6O.ClH/c1-15(2)18-13-26-28-21(25-11-16-6-4-3-5-7-16)10-20(27-22(18)28)24-12-17-8-9-23-14-19(17)29;/h3-7,10,13,15,17,19,23,25,29H,8-9,11-12,14H2,1-2H3,(H,24,27);1H/t17-,19+;/m1./s1
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| Chemical Name |
(3R,4R)-4-[[[7-(benzylamino)-3-propan-2-ylpyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol;hydrochloride
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| Synonyms |
PPDA-001; PPDA-001; PPDA-001; GTPL 9903; GTPL9903; GTPL-9903; ICEC0942; ICEC 0942; ICEC-0942; CT7001; CT 7001;CT-7001
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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. |
| 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: 86~100 mg/mL (199.6~232.0 mM)
Ethanol: 15 mg/mL (~34.8 mM) Water: 86 mg/mL (~199.6 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.80 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% 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 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.80 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.80 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 100 mg/mL (232.03 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3203 mL | 11.6017 mL | 23.2035 mL | |
| 5 mM | 0.4641 mL | 2.3203 mL | 4.6407 mL | |
| 10 mM | 0.2320 mL | 1.1602 mL | 2.3203 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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